Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Epidemiology of the inherited cardiomyopathies

Nature Reviews Cardiology volume 18, pages 22–36 (2021)Cite this article

Subjects

Abstract

In the absence of contemporary, population-based epidemiological studies, estimates of the incidence and prevalence of the inherited cardiomyopathies have been derived from screening studies, most often of young adult populations, to assess cardiovascular risk or to detect the presence of disease in athletes or military recruits. The global estimates for hypertrophic cardiomyopathy (1/500 individuals), dilated cardiomyopathy (1/250) and arrhythmogenic right ventricular cardiomyopathy (1/5,000) are probably conservative given that only individuals who fulfil diagnostic criteria would have been included. This caveat is highly relevant because a substantial minority or even a majority of individuals who carry disease-causing genetic variants and are at risk of disease complications have incomplete and/or late-onset disease expression. The genetic literature on cardiomyopathy, which is often focused on the identification of genetic variants, has been biased in favour of pedigrees with higher penetrance. In clinical practice, an abnormal electrocardiogram with normal or non-diagnostic imaging results is a common finding for the sarcomere variants that cause hypertrophic cardiomyopathy, the titin and sarcomere variants that cause dilated cardiomyopathy and the desmosomal variants that cause either arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy. Therefore, defining the genetic epidemiology is also challenging given the overlapping phenotypes, incomplete and age-related expression, and highly variable penetrance even within individual families carrying the same genetic variant.

Key points

  • Contemporary age-adjusted and sex-adjusted, population-based epidemiological studies of the incidence and prevalence of the inherited cardiomyopathies are lacking.

  • Contemporary understanding of the genetic epidemiology of the inherited cardiomyopathies reveals incomplete and age-related disease expression and low penetrance for the majority of the genetic variants associated with these conditions.

  • Current prevalence estimates for hypertrophic cardiomyopathy (1/500) and dilated cardiomyopathy (1/250) are on the basis of screening studies, mainly in healthy young adults, and probably underestimate the true prevalence of disease and the risk of disease-related complications.

  • Prevalence estimates for arrhythmogenic cardiomyopathy (1/2,000 to 1/5,000) are on the basis of extrapolation from allele frequencies of genetic variants and the generally low penetrance of most of these variants.

  • Inherited restrictive cardiomyopathy is rare and usually associated with hypertrophic, dilated, infiltrative or arrhythmic cardiomyopathy, sometimes with musculoskeletal abnormalities in other members of the family.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Male patient aged 19 years with hypertrophic cardiomyopathy.
Fig. 2: Penetrance and disease expression vary between genes and between pathogenic variants.
Fig. 3: Echocardiographic evaluation at initial screening and during follow-up of asymptomatic relatives of probands with DCM.
Fig. 4: Prevalence of truncating variants in TTN in comparison with the prevalence of inherited forms of cardiomyopathy.

Similar content being viewed by others

References

  1. McKenna, W. & Elliott, P. in Goldman–Cecil Medicine 26th edn Ch. 54 (eds Goldman, L. & Schaffer, A. I.) 297–314 (Elsevier, 2019).

  2. Marian, A. J. & Braunwald, E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ. Res. 121, 749–770 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Maron, B. J. Clinical course and management of hypertrophic cardiomyopathy. N. Engl. J. Med. 379, 655–668 (2018).

    PubMed  Google Scholar 

  4. Hershberger, R. E., Hedges, D. J. & Morales, A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat. Rev. Cardiol. 10, 531–547 (2013).

    CAS  PubMed  Google Scholar 

  5. Peters, S., Kumar, S., Elliott, P., Kalman, J. M. & Fatkin, D. Arrhythmic genotypes in familial dilated cardiomyopathy: implications for genetic testing and clinical management. Heart Lung Circ. 28, 31–38 (2019).

    PubMed  Google Scholar 

  6. Towbin, J. A. et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm 16, e301–e372 (2019).

    PubMed  Google Scholar 

  7. Elliott, P. M. et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the task force for the diagnosis and management of hypertrophic cardiomyopathy of the European Society of Cardiology (ESC). Eur. Heart J. 35, 2733–2779 (2014).

    PubMed  Google Scholar 

  8. Redfield, M. M. et al. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA 289, 194–202 (2003).

    PubMed  Google Scholar 

  9. Wang, T. J. et al. Natural history of asymptomatic left ventricular systolic dysfunction in the community. Circulation 108, 977–982 (2003).

    PubMed  Google Scholar 

  10. Yeboah, J. et al. Prognosis of individuals with asymptomatic left ventricular systolic dysfunction in the multi-ethnic study of atherosclerosis (MESA). Circulation 126, 2713–2719 (2012).

    PubMed  PubMed Central  Google Scholar 

  11. Fitzpatrick, A. P., Shapiro, L. M., Rickards, A. F. & Poole-Wilson, P. A. Familial restrictive cardiomyopathy with atrioventricular block and skeletal myopathy. Br. Heart J. 63, 114–118 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Coats, C. J. & Hollman, A. Hypertrophic cardiomyopathy: lessons from history. Heart 94, 1258–1263 (2008).

    CAS  PubMed  Google Scholar 

  13. [No authors listed]. Report of the WHO/ISFC task force on the definition and classification of cardiomyopathies. Br. Heart J. 44, 672–673 (1980).

    Google Scholar 

  14. Richardson, P. et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology task force on the definition and classification of cardiomyopathies. Circulation 93, 841–842 (1996).

    CAS  PubMed  Google Scholar 

  15. Elliott, P. et al. Classification of the cardiomyopathies: a position statement from the European Society of Cardiology working group on myocardial and pericardial diseases. Eur. Heart J. 29, 270–276 (2008).

    PubMed  Google Scholar 

  16. van Waning, J. I. et al. Genetics, clinical features, and long-term outcome of noncompaction cardiomyopathy. J. Am. Coll. Cardiol. 71, 711–722 (2018).

    PubMed  Google Scholar 

  17. Maron, B. J. & Epstein, S. E. Hypertrophic cardiomyopathy: a discussion of nomenclature. Am. J. Cardiol. 43, 1242–1244 (1979).

    CAS  PubMed  Google Scholar 

  18. McLeod, C. J. et al. Outcome of patients with hypertrophic cardiomyopathy and a normal electrocardiogram. J. Am. Coll. Cardiol. 54, 229–233 (2009).

    PubMed  Google Scholar 

  19. Gersh, B. J. et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation 124, 2761–2796 (2011).

    PubMed  Google Scholar 

  20. Ingles, J. et al. Nonfamilial hypertrophic cardiomyopathy: prevalence, natural history, and clinical implications. Circ. Cardiovasc. Genet. 10, e001620 (2017).

    CAS  PubMed  Google Scholar 

  21. Lewis, J. F. & Maron, B. J. Diversity of patterns of hypertrophy in patients with systemic hypertension and marked left ventricular wall thickening. Am. J. Cardiol. 65, 874–881 (1990).

    CAS  PubMed  Google Scholar 

  22. Dungu, J. et al. The electrocardiographic features associated with cardiac amyloidosis of variant transthyretin isoleucine 122 type in Afro-Caribbean patients. Am. Heart J. 164, 72–79 (2012).

    CAS  PubMed  Google Scholar 

  23. Hill, M. N. et al. Hypertension care and control in underserved urban African American men: behavioral and physiologic outcomes at 36 months. Am. J. Hypertens. 16, 906–913 (2003).

    PubMed  Google Scholar 

  24. Braunwald, E., Brockenbrough, E. C. & Morrow, A. G. Hypertrophic subaortic stenosis — a broadened concept. Circulation 26, 161–165 (1962).

    CAS  PubMed  Google Scholar 

  25. Ho, C. Y. et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy: insights from the sarcomeric human cardiomyopathy registry (SHaRe). Circulation 138, 1387–1398 (2018).

    PubMed  PubMed Central  Google Scholar 

  26. Maron, B. J. et al. Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referral-based patient population. Circulation 102, 858–864 (2000).

    CAS  PubMed  Google Scholar 

  27. Finocchiaro, G. et al. Sudden death can be the first manifestation of hypertrophic cardiomyopathy: data from a United Kingdom pathology registry. JACC Clin. Electrophysiol. 5, 252–254 (2019).

    PubMed  Google Scholar 

  28. Hada, Y. et al. Prevalence of hypertrophic cardiomyopathy in a population of adult Japanese workers as detected by echocardiographic screening. Am. J. Cardiol. 59, 183–184 (1987).

    CAS  PubMed  Google Scholar 

  29. Codd, M. B., Sugrue, D. D., Gersh, B. J. & Melton, L. J. III. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975–1984. Circulation 80, 564–572 (1989).

    CAS  PubMed  Google Scholar 

  30. Maron, B. J. et al. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA study. Coronary artery risk development in (young) adults. Circulation 92, 785–789 (1995).

    CAS  PubMed  Google Scholar 

  31. Maron, B. J., Mathenge, R., Casey, S. A., Poliac, L. C. & Longe, T. F. Clinical profile of hypertrophic cardiomyopathy identified de novo in rural communities. J. Am. Coll. Cardiol. 33, 1590–1595 (1999).

    CAS  PubMed  Google Scholar 

  32. Corrado, D., Basso, C., Schiavon, M. & Thiene, G. Screening for hypertrophic cardiomyopathy in young athletes. N. Engl. J. Med. 339, 364–369 (1998).

    CAS  PubMed  Google Scholar 

  33. Miura, K. et al. Epidemiology of idiopathic cardiomyopathy in Japan: results from a nationwide survey. Heart 87, 126–130 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Nistri, S. et al. Screening for hypertrophic cardiomyopathy in a young male military population. Am. J. Cardiol. 91, 1021–1023 (2003).

    PubMed  Google Scholar 

  35. Maron, B. J. et al. Prevalence of hypertrophic cardiomyopathy in a population-based sample of American Indians aged 51 to 77 years (the Strong Heart study). Am. J. Cardiol. 93, 1510–1514 (2004).

    PubMed  Google Scholar 

  36. Zou, Y. et al. Prevalence of idiopathic hypertrophic cardiomyopathy in China: a population-based echocardiographic analysis of 8080 adults. Am. J. Med. 116, 14–18 (2004).

    PubMed  Google Scholar 

  37. Maro, E. E., Janabi, M. & Kaushik, R. Clinical and echocardiographic study of hypertrophic cardiomyopathy in Tanzania. Trop. Doct. 36, 225–227 (2006).

    CAS  PubMed  Google Scholar 

  38. Morita, H. et al. Single-gene mutations and increased left ventricular wall thickness in the community: the Framingham Heart study. Circulation 113, 2697–2705 (2006).

    PubMed  Google Scholar 

  39. Ma, J. Z. et al. Cardiovascular pre-participation screening of young competitive athletes for prevention of sudden death in China. J. Sci. Med. Sport 10, 227–233 (2007).

    PubMed  Google Scholar 

  40. Ng, C. T. et al. Prevalence of hypertrophic cardiomyopathy on an electrocardiogram-based pre-participation screening programme in a young male south-east Asian population: results from the Singapore armed forces electrocardiogram and echocardiogram screening protocol. Europace 13, 883–888 (2011).

    PubMed  Google Scholar 

  41. Eberly, L. A. et al. Association of race with disease expression and clinical outcomes among patients with hypertrophic cardiomyopathy. JAMA Cardiol. 5, 83–91 (2019).

    PubMed Central  Google Scholar 

  42. Semsarian, C., Ingles, J., Maron, M. S. & Maron, B. J. New perspectives on the prevalence of hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 65, 1249–1254 (2015).

    PubMed  Google Scholar 

  43. Lipshultz, S. E. et al. The incidence of pediatric cardiomyopathy in two regions of the United States. N. Engl. J. Med. 348, 1647–1655 (2003).

    PubMed  Google Scholar 

  44. Nugent, A. W. et al. The epidemiology of childhood cardiomyopathy in Australia. N. Engl. J. Med. 348, 1639–1646 (2003).

    PubMed  Google Scholar 

  45. Towbin, J. A. et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 296, 1867–1876 (2006).

    CAS  PubMed  Google Scholar 

  46. Arola, A. et al. Epidemiology of idiopathic cardiomyopathies in children and adolescents. A nationwide study in Finland. Am. J. Epidemiol. 146, 385–393 (1997).

    CAS  PubMed  Google Scholar 

  47. Cirino, A. L. et al. Hypertrophic Cardiomyopathy Overview (University of Washington, 1993).

  48. Alfares, A. A. et al. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet. Med. 17, 880–888 (2015).

    PubMed  Google Scholar 

  49. Sharma, S. et al. Physiologic limits of left ventricular hypertrophy in elite junior athletes: relevance to differential diagnosis of athlete’s heart and hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 40, 1431–1436 (2002).

    PubMed  Google Scholar 

  50. Niimura, H. et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N. Engl. J. Med. 338, 1248–1257 (1998).

    CAS  PubMed  Google Scholar 

  51. Mogensen, J. et al. Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 44, 2315–2325 (2004).

    CAS  PubMed  Google Scholar 

  52. Rapezzi, C. et al. Diagnostic work-up in cardiomyopathies: bridging the gap between clinical phenotypes and final diagnosis. A position statement from the ESC working group on myocardial and pericardial diseases. Eur. Heart J. 34, 1448–1458 (2013).

    PubMed  Google Scholar 

  53. Waller, B. F. Hearts of the “oldest old”. Mayo Clin. Proc. 63, 625–627 (1988).

    CAS  PubMed  Google Scholar 

  54. Neubauer, S. et al. Distinct subgroups in hypertrophic cardiomyopathy in the NHLBI HCM registry. J. Am. Coll. Cardiol. 74, 2333–2345 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Mestroni, L. et al. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart muscle disease study group. J. Am. Coll. Cardiol. 34, 181–190 (1999).

    CAS  PubMed  Google Scholar 

  56. Michels, V. V. et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N. Engl. J. Med. 326, 77–82 (1992).

    CAS  PubMed  Google Scholar 

  57. Schultheiss, H. P. et al. Dilated cardiomyopathy. Nat. Rev. Dis. Prim. 5, 32 (2019).

    PubMed  Google Scholar 

  58. Henry, W. L., Gardin, J. M. & Ware, J. H. Echocardiographic measurements in normal subjects from infancy to old age. Circulation 62, 1054–1061 (1980).

    CAS  PubMed  Google Scholar 

  59. Mahon, N. G. et al. Echocardiographic evaluation in asymptomatic relatives of patients with dilated cardiomyopathy reveals preclinical disease. Ann. Intern. Med. 143, 108–115 (2005).

    PubMed  Google Scholar 

  60. Davies, M. et al. Prevalence of left-ventricular systolic dysfunction and heart failure in the Echocardiographic Heart of England Screening study: a population based study. Lancet 358, 439–444 (2001).

    CAS  PubMed  Google Scholar 

  61. Wang, T. J., Levy, D., Benjamin, E. J. & Vasan, R. S. The epidemiology of “asymptomatic” left ventricular systolic dysfunction: implications for screening. Ann. Intern. Med. 138, 907–916 (2003).

    PubMed  Google Scholar 

  62. Seidelmann, S. B. et al. Familial dilated cardiomyopathy diagnosis is commonly overlooked at the time of transplant listing. J. Heart Lung Transplant. 35, 474–480 (2016).

    PubMed  Google Scholar 

  63. Rusconi, P. et al. Differences in presentation and outcomes between children with familial dilated cardiomyopathy and children with idiopathic dilated cardiomyopathy: a report from the pediatric cardiomyopathy registry study group. Circ. Heart Fail. 10, e002637 (2017).

    PubMed  PubMed Central  Google Scholar 

  64. Norton, N. et al. Evaluating pathogenicity of rare variants from dilated cardiomyopathy in the exome era. Circ. Cardiovasc. Genet. 5, 167–174 (2012).

    PubMed  PubMed Central  Google Scholar 

  65. Muntoni, F. et al. Brief report: deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. N. Engl. J. Med. 329, 921–925 (1993).

    CAS  PubMed  Google Scholar 

  66. Towbin, J. A. et al. X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation 87, 1854–1865 (1993).

    CAS  PubMed  Google Scholar 

  67. Hearn, T. et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome. Nat. Genet. 31, 79–83 (2002).

    CAS  PubMed  Google Scholar 

  68. Santorelli, F. M. et al. Maternally inherited cardiomyopathy and hearing loss associated with a novel mutation in the mitochondrial tRNA(Lys) gene (G8363A). Am. J. Hum. Genet. 58, 933–939 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Bonne, G. et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat. Genet. 21, 285–288 (1999).

    CAS  PubMed  Google Scholar 

  70. Peretto, G. et al. Cardiac and neuromuscular features of patients with LMNA-related cardiomyopathy. Ann. Intern. Med. 171, 458–463 (2019).

    PubMed  Google Scholar 

  71. Marcus, F. I. et al. Right ventricular dysplasia: a report of 24 adult cases. Circulation 65, 384–398 (1982).

    CAS  PubMed  Google Scholar 

  72. Basso, C. et al. Arrhythmogenic right ventricular cardiomyopathy. Circulation 94, 983–991 (1996).

    CAS  PubMed  Google Scholar 

  73. Basso, C., Corrado, D. & Thiene, G. Arrhythmogenic right ventricular cardiomyopathy: what’s in a name? From a congenital defect (dysplasia) to a genetically determined cardiomyopathy (dystrophy). Am. J. Cardiol. 106, 275–277 (2010).

    PubMed  Google Scholar 

  74. Awad, M. M., Calkins, H. & Judge, D. P. Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nat. Clin. Pract. Cardiovasc. Med. 5, 258–267 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Norman, M. et al. Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Circulation 112, 636–642 (2005).

    CAS  PubMed  Google Scholar 

  76. McKenna, W. J. et al. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task force of the working group myocardial and pericardial disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. Br. Heart J. 71, 215–218 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Marcus, F. I. et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Eur. Heart J. 31, 806–814 (2010).

    PubMed  PubMed Central  Google Scholar 

  78. Platonov, P. G. et al. High interobserver variability in the assessment of epsilon waves: implications for diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm 13, 208–216 (2016).

    PubMed  Google Scholar 

  79. Gerull, B. et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat. Genet. 36, 1162–1164 (2004).

    CAS  PubMed  Google Scholar 

  80. Landrum, M. J. et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 42, D980–D985 (2013).

    PubMed  PubMed Central  Google Scholar 

  81. McKenna, W. J., Maron, B. J. & Thiene, G. Classification, epidemiology, and global burden of cardiomyopathies. Circ. Res. 121, 722–730 (2017).

    CAS  PubMed  Google Scholar 

  82. Thiene, G., Nava, A., Corrado, D., Rossi, L. & Pennelli, N. Right ventricular cardiomyopathy and sudden death in young people. N. Engl. J. Med. 318, 129–133 (1988).

    CAS  PubMed  Google Scholar 

  83. Peters, S., Trümmel, M. & Meyners, W. Prevalence of right ventricular dysplasia-cardiomyopathy in a non-referral hospital. Int. J. Cardiol. 97, 499–501 (2004).

    PubMed  Google Scholar 

  84. Merner, N. D. 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, 809–821 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Sliwa, K., Damasceno, A. & Mayosi, B. M. Epidemiology and etiology of cardiomyopathy in Africa. Circulation 112, 3577–3583 (2005).

    PubMed  Google Scholar 

  86. Munclinger, M. J., Patel, J. J. & Mitha, A. S. Follow-up of patients with arrhythmogenic right ventricular cardiomyopathy dysplasia. S. Afr. Med. J. 90, 61–68 (2000).

    CAS  PubMed  Google Scholar 

  87. Hendricks, N., Watkins, D. A. & Mayosi, B. M. Lessons from the first report of the arrhythmogenic right ventricular cardiomyopathy registry of South Africa. Cardiovasc. J. Afr. 21, 129–130 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Protonotarios, N. et al. Cardiac abnormalities in familial palmoplantar keratosis. Br. Heart J. 56, 321–326 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Coonar, A. S. et al. Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (Naxos disease) maps to 17q21. Circulation 97, 2049–2058 (1998).

    CAS  PubMed  Google Scholar 

  90. McKoy, G. et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 355, 2119–2124 (2000).

    CAS  PubMed  Google Scholar 

  91. Norgett, E. E. et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum. Mol. Genet. 9, 2761–2766 (2000).

    CAS  PubMed  Google Scholar 

  92. Awad, M. M. et al. DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am. J. Hum. Genet. 79, 136–142 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Syrris, P. et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2. Am. J. Hum. Genet. 79, 978–984 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Pilichou, K. et al. Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 113, 1171–1179 (2006).

    CAS  PubMed  Google Scholar 

  95. Ahmad, F. et al. Localization of a gene responsible for arrhythmogenic right ventricular dysplasia to chromosome 3p23. Circulation 98, 2791–2795 (1998).

    CAS  PubMed  Google Scholar 

  96. Milting, H. et al. The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus. Eur. Heart J. 36, 872–881 (2014).

    PubMed  Google Scholar 

  97. Capell, B. C. & Collins, F. S. Human laminopathies: nuclei gone genetically awry. Nat. Rev. Genet. 7, 940–952 (2006).

    CAS  PubMed  Google Scholar 

  98. Fatkin, D. et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N. Engl. J. Med. 341, 1715–1724 (1999).

    CAS  PubMed  Google Scholar 

  99. Hasselberg, N. E. et al. Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation. Eur. Heart J. 39, 853–860 (2017).

    PubMed Central  Google Scholar 

  100. van Tintelen, J. P. et al. High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics. Am. Heart J. 154, 1130–1139 (2007).

    PubMed  Google Scholar 

  101. Quarta, G. et al. Mutations in the lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy. Eur. Heart J. 33, 1128–1136 (2012).

    CAS  PubMed  Google Scholar 

  102. Tiso, N. et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum. Mol. Genet. 10, 189–194 (2001).

    CAS  PubMed  Google Scholar 

  103. Priori, S. G. et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 106, 69–74 (2002).

    CAS  PubMed  Google Scholar 

  104. Schmitt, J. P. et al. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science 299, 1410–1413 (2003).

    CAS  PubMed  Google Scholar 

  105. Haghighi, K. et al. Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. J. Clin. Invest. 111, 869–876 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Haghighi, K. et al. A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy. Proc. Natl Acad. Sci. USA 103, 1388–1393 (2006).

    CAS  PubMed  Google Scholar 

  107. van der Zwaag, P. 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, 1199–1207 (2012).

    PubMed  PubMed Central  Google Scholar 

  108. Groeneweg, J. 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, 437–446 (2015).

    CAS  PubMed  Google Scholar 

  109. van Spaendonck-Zwarts, K. Y. et al. Recurrent and founder mutations in the Netherlands: the cardiac phenotype of DES founder mutations p.S13F and p.N342D. Neth. Heart J. 20, 219–228 (2012).

    PubMed  PubMed Central  Google Scholar 

  110. Lorenzon, A. et al. Desmin mutations and arrhythmogenic right ventricular cardiomyopathy. Am. J. Cardiol. 111, 400–405 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Remme, C. A. Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects. J. Physiol. 591, 4099–4116 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Olson, T. M. et al. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA 293, 447–454 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. te Riele, A. S. J. M. et al. Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis. Cardiovasc. Res. 113, 102–111 (2017).

    Google Scholar 

  114. Dalal, D. et al. Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J. Am. Coll. Cardiol. 48, 1416–1424 (2006).

    CAS  PubMed  Google Scholar 

  115. Quarta, G. et al. Familial evaluation in arrhythmogenic right ventricular cardiomyopathy. Circulation 123, 2701–2709 (2011).

    PubMed  Google Scholar 

  116. Dalal, D. et al. Arrhythmogenic right ventricular dysplasia: a United States experience. Circulation 112, 3823–3832 (2005).

    PubMed  Google Scholar 

  117. Xu, T. et al. Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. J. Am. Coll. Cardiol. 55, 587–597 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Gifford, C. A. et al. Oligogenic inheritance of a human heart disease involving a genetic modifier. Science 364, 865–870 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. James, C. A. et al. Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. J. Am. Coll. Cardiol. 62, 1290–1297 (2013).

    PubMed  Google Scholar 

  120. Chelko, S. P. et al. Central role for GSK3β in the pathogenesis of arrhythmogenic cardiomyopathy. JCI Insight 1, e85923 (2016).

    PubMed Central  Google Scholar 

  121. Martherus, R. et al. Accelerated cardiac remodeling in desmoplakin transgenic mice in response to endurance exercise is associated with perturbed Wnt/β-catenin signaling. Am. J. Physiol. Heart Circ. Physiol. 310, H174–H187 (2016).

    PubMed  Google Scholar 

  122. Carruth, E. D. et al. Prevalence and electronic health record-based phenotype of loss-of-function genetic variants in arrhythmogenic right ventricular cardiomyopathy-associated genes. Circ. Genom. Precis. Med. 12, e002579 (2019).

    PubMed  PubMed Central  Google Scholar 

  123. van Lint, F. H. M. et al. Arrhythmogenic right ventricular cardiomyopathy-associated desmosomal variants are rarely de novo. Circ. Genom. Precis. Med. 12, e002467 (2019).

    PubMed  Google Scholar 

  124. Qiu, X. et al. Mutations of plakophilin-2 in Chinese with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am. J. Cardiol. 103, 1439–1444 (2009).

    CAS  PubMed  Google Scholar 

  125. Chen, L. et al. A founder homozygous DSG2 variant in east Asia results in ARVC with full penetrance and heart failure phenotype. Int. J. Cardiol. 274, 263–270 (2019).

    PubMed  Google Scholar 

  126. Kubo, T. et al. Prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy with restrictive phenotype. J. Am. Coll. Cardiol. 49, 2419–2426 (2007).

    CAS  PubMed  Google Scholar 

  127. Mogensen, J. et al. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J. Clin. Invest. 111, 209–216 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Kittleson, M. M. et al. Cardiac amyloidosis: evolving diagnosis and management: a scientific statement from the American Heart Association. Circulation 142, e7–e22 (2020).

    PubMed  Google Scholar 

  129. Brodehl, A. et al. Mutations in FLNC are associated with familial restrictive cardiomyopathy. Hum. Mutat. 37, 269–279 (2016).

    CAS  PubMed  Google Scholar 

  130. Tucker, N. R. et al. Novel mutation in FLNC (filamin C) causes familial restrictive cardiomyopathy. Circ. Cardiovasc. Genet. 10, e001780 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Bermudez-Jimenez, F. J. et al. Novel desmin mutation p.Glu401Asp impairs filament formation, disrupts cell membrane integrity, and causes severe arrhythmogenic left ventricular cardiomyopathy/dysplasia. Circulation 137, 1595–1610 (2018).

    CAS  PubMed  Google Scholar 

  132. Brodehl, A. et al. Restrictive cardiomyopathy is caused by a novel homozygous desmin (DES) mutation p.Y122H leading to a severe filament assembly defect. Genes 10, 918 (2019).

    CAS  PubMed Central  Google Scholar 

  133. Muchtar, E., Blauwet, L. A. & Gertz, M. A. Restrictive cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ. Res. 121, 819–837 (2017).

    CAS  PubMed  Google Scholar 

  134. Jenni, R. et al. Persisting myocardial sinusoids of both ventricles as an isolated anomaly: echocardiographic, angiographic, and pathologic anatomical findings. Cardiovasc. Intervent. Radiol. 9, 127–131 (1986).

    CAS  PubMed  Google Scholar 

  135. Kawel, N. et al. Trabeculated (noncompacted) and compact myocardium in adults: the multi-ethnic study of atherosclerosis. Circ. Cardiovasc. Imaging 5, 357–366 (2012).

    PubMed  PubMed Central  Google Scholar 

  136. Petersen, S. E. et al. Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging. J. Am. Coll. Cardiol. 46, 101–105 (2005).

    PubMed  Google Scholar 

  137. Weir-McCall, J. R. et al. Left ventricular noncompaction: anatomical phenotype or distinct cardiomyopathy? J. Am. Coll. Cardiol. 68, 2157–2165 (2016).

    PubMed  PubMed Central  Google Scholar 

  138. Ross, S. B. et al. A systematic review and meta-analysis of the prevalence of left ventricular non-compaction in adults. Eur. Heart J. 41, 1428–1436 (2020).

    PubMed  Google Scholar 

  139. Hershberger, R. E. et al. Genetic evaluation of cardiomyopathy — a Heart Failure Society of America practice guideline. J. Card. Fail. 24, 281–302 (2018).

    PubMed  Google Scholar 

  140. Jarcho, J. A. et al. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. N. Engl. J. Med. 321, 1372–1378 (1989).

    CAS  PubMed  Google Scholar 

  141. Geisterfer-Lowrance, A. A. et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell 62, 999–1006 (1990).

    CAS  PubMed  Google Scholar 

  142. Epstein, N. D., Cohn, G. M., Cyran, F. & Fananapazir, L. Differences in clinical expression of hypertrophic cardiomyopathy associated with two distinct mutations in the beta-myosin heavy chain gene. A 908Leu–Val mutation and a 403Arg–Gln mutation. Circulation 86, 345–352 (1992).

    CAS  PubMed  Google Scholar 

  143. Fananapazir, L. & Epstein, N. D. Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical beta-myosin heavy chain gene mutations. Circulation 89, 22–32 (1994).

    CAS  PubMed  Google Scholar 

  144. Karibe, A. et al. Hypertrophic cardiomyopathy caused by a novel alpha-tropomyosin mutation (V95A) is associated with mild cardiac phenotype, abnormal calcium binding to troponin, abnormal myosin cycling, and poor prognosis. Circulation 103, 65–71 (2001).

    CAS  PubMed  Google Scholar 

  145. Sheikh, N. et al. Comparison of electrocardiographic criteria for the detection of cardiac abnormalities in elite black and white athletes. Circulation 129, 1637–1649 (2014).

    PubMed  Google Scholar 

  146. Maron, B. J., Spirito, P., Wesley, Y. & Arce, J. Development and progression of left ventricular hypertrophy in children with hypertrophic cardiomyopathy. N. Engl. J. Med. 315, 610–614 (1986).

    CAS  PubMed  Google Scholar 

  147. Baig, M. K. et al. Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives and may represent early disease. J. Am. Coll. Cardiol. 31, 195–201 (1998).

    CAS  PubMed  Google Scholar 

  148. Parks, S. B. et al. Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. Am. Heart J. 156, 161–169 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are supported by a grant from the Leducq Foundation (W.J.M. and D.P.J.).

Author information

Authors and Affiliations

  1. Institute of Cardiovascular Science, University College London, London, UK

    William J. McKenna

  2. Heart Hospital, Hamad Medical Corporation, Doha, Qatar

    William J. McKenna

  3. Section of Advanced HF & Transplant Cardiology, Medical University of South Carolina, Charleston, SC, USA

    Daniel P. Judge

Authors
  1. William J. McKenna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel P. Judge
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors contributed to all aspects of preparing the manuscript.

Corresponding author

Correspondence to William J. McKenna.

Ethics declarations

Competing interests

D.P.J. has received payments as a consultant from 4D Molecular Therapeutics, ADRx Pharma and Pfizer, and has received research funding from Array Biopharma and Eidos Therapeutics. W.J.M. declares no competing interests.

Additional information

Peer review information

Nature Reviews Cardiology thanks L. Mestroni, C. Semsarian and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/

gnomAD: https://gnomad.broadinstitute.org/

Supplementary information

Glossary

Mendelian pattern

Inheritance pattern of single-gene disorders with high penetrance, including autosomal dominant, autosomal recessive and X-linked.

Incomplete disease expression

A genetic predisposition to a disease that does not cause manifestations that are sufficient to meet the criteria for diagnosis of the condition.

Age-related penetrance

A genetic predisposition that does not cause phenotypic manifestations until later in life.

Epsilon waves

A feature of the electrocardiogram defined as a reproducible low-amplitude signal between the end of the QRS complex and the onset of the T wave in the right precordial leads (V1 to V3).

Variants of uncertain significance

DNA variants that do not meet criteria for being classified as pathogenic, likely pathogenic, benign or likely benign, according to the joint recommendation of the American College of Medical Genetics and the Association for Molecular Pathology.

Desmosome

Subcellular structures mediating intercellular junctions for many types of cell, particularly cardiomyocytes.

Haplotype

Sets of chromosomal markers for sections of DNA that segregate in families.

Digenic heterozygosity

The presence of one pathogenic variant in each of two different genes, each of which contributes to the phenotype.

Oligogenic inheritance

A constellation of more than two DNA variants, each of which contributes to the phenotype.

Allele frequency

The number of times that a variant is present in a large population divided by the total number of copies of all variants at that particular locus.

Hypertrabeculation

An increased ratio of non-compacted to compacted areas of the left ventricle; also referred to as non-compaction.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McKenna, W.J., Judge, D.P. Epidemiology of the inherited cardiomyopathies. Nat Rev Cardiol 18, 22–36 (2021). https://doi.org/10.1038/s41569-020-0428-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41569-020-0428-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing