The genetics of cardiomyopathy: Genotyping and genetic counseling

  • Steven J. Fowler
  • Carlo Napolitano
  • Silvia G. Priori

Opinion statement

Three decades of ongoing research into the identification of genes responsible for both cardiomyopathies and ion channel diseases has facilitated a progressive understanding of the pathophysiology of inherited arrhythmogenic diseases. Recent discoveries in the area of genetics promise to significantly change the current clinical practice of cardiology, as rapid advances in technology and a coincident reduction of costs associated with sequencing have pushed the “translation“ of genomic information from bench to bedside. In turn, clinicians have at their disposal new tools for more accurate diagnosis of diseases, as well as for better calculation of health risks for affected families. It is clear, however, that the integration of genetic analysis into frontline clinical cardiology has not yet occurred, especially for heritable cardiomyopathic processes; no one simplified method exists for diagnosing these complex cardiac disease states. It therefore is important to assess the present and future roles of genetic analysis and counseling in clinical practice and how to assist the transition of genetic screening into current care to ensure the appropriate practical use of genetic tests in the routine clinical setting. The purpose of this discussion is to provide a concise review of recent developments in the field of heritable cardiomyopathies, with specific regard to genetic testing and genetic counseling.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Priori SG, Barhanin J, Hauer RN, et al.: Genetic and molecular basis of cardiac arrhythmias: impact on clinical management parts I and II. Circulation 1999, 99:518–528.PubMedGoogle Scholar
  2. 2.
    Lehnart SE, Ackerman MJ, Benson DW Jr, et al.: Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel function. Circulation 2007, 116:2325–2345.CrossRefPubMedGoogle Scholar
  3. 3.
    Priori SG, Napolitano C, Vicentini A: Inherited arrhythmia syndromes: applying the molecular biology and genetic to the clinical management. J Interv Card Electrophysiol 2003, 9:93–101.CrossRefPubMedGoogle Scholar
  4. 4.
    Priori SG, Napolitano C: Role of genetic analyses in cardiology: part I: mendelian diseases: cardiac channelopathies. Circulation 2006, 113:1130–1135.CrossRefPubMedGoogle Scholar
  5. 5.
    Hershberger RE, Lindenfeld J, Mestroni L, et al.; Heart Failure Society of America: Genetic evaluation of cardiomyopathy—a Heart Failure Society of America practice guideline. J Card Fail 2009, 15:83–97.CrossRefPubMedGoogle Scholar
  6. 6.
    Morales A, Cowan J, Dagua J, Hershberger RE: Family history: an essential tool for cardiovascular genetic medicine. Congest Heart Fail 2008, 14:37–45.CrossRefPubMedGoogle Scholar
  7. 7.
    van der Roest WP, Pennings JM, Bakker M, et al.: Family letters are an effective way to inform relatives about inherited cardiac disease. Am J Med Genet A 2009, 149A:357–363.CrossRefPubMedGoogle Scholar
  8. 8.
    Richard P, Charron P, Carrier L, et al.; EUROGENE Heart Failure Project: Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003, 107:2227–2232.CrossRefPubMedGoogle Scholar
  9. 9.
    Keren A, Syrris P, McKenna WJ: Hypertrophic cardiomyopathy: the genetic determinants of clinical disease expression. Nat Clin Pract Cardiovasc Med 2008, 5:158–168.CrossRefPubMedGoogle Scholar
  10. 10.
    van Dijk SJ, Dooijes D, dos Remedios C, et al.: Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy: haploinsufficiency, deranged phosphorylation, and cardiomyocyte dysfunction. Circulation 2009, 119:1473–1483.CrossRefPubMedGoogle Scholar
  11. 11.
    Maron BJ, Gardin JM, Flack JM, 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 1995, 92:785–789.PubMedGoogle Scholar
  12. 12.
    Maron BJ, McKenna WJ, Danielson GK, et al.: Task Force on Clinical Expert Consensus Documents, American College of Cardiology; Committee for Practice Guidelines, European Society of Cardiology; American College of Cardiology/European Society of Cardiology: A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2003, 42:1687–1713.CrossRefPubMedGoogle Scholar
  13. 13.
    Priori SG: Inherited arrhythmogenic diseases: the complexity beyond monogenic disorders. Circ Res 2004, 94:140–145.CrossRefPubMedGoogle Scholar
  14. 14.
    Watkins H, Rosenzweig A, Hwang DS, et al.: Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med 1992, 326:1108–1114.PubMedCrossRefGoogle Scholar
  15. 15.
    Charron P, Dubourg O, Desnos M, et al.: Genotype-phenotype correlations in familial hypertrophic cardiomyopathy. A comparison between mutations in the cardiac protein-C and the beta-myosin heavy chain genes. Eur Heart J 1998, 19:139–145.CrossRefPubMedGoogle Scholar
  16. 16.
    Van Driest SL, Vasile VC, Ommen SR, et al.: Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol 2004, 44:1903–1910.CrossRefPubMedGoogle Scholar
  17. 17.
    Ehlermann P, Weichenhan D, Zehelein J, et al.: Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene. BMC Med Genet 2008, 9:95.CrossRefPubMedGoogle Scholar
  18. 18.
    Watkins H, McKenna WJ, Thierfelder L, et al.: Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med 1995, 332:1058–1064.CrossRefPubMedGoogle Scholar
  19. 19.
    Varnava AM, Elliott PM, Baboonian C, et al.: Hypertrophic cardiomyopathy: histopathological features of sudden death in cardiac troponin T disease. Circulation 2001, 104:1380–1384.CrossRefPubMedGoogle Scholar
  20. 20.
    Coats CJ, Elliott PM: Current management of hypertrophic cardiomyopathy. Curr Treat Options Cardiovasc Med 2008, 10:496–504.CrossRefPubMedGoogle Scholar
  21. 21.
    Marian AJ: Genetic determinants of cardiac hypertrophy. Curr Opin Cardiol 2008, 23:199–205.CrossRefPubMedGoogle Scholar
  22. 22.
    Watkins H, Ashrafian H, McKenna WJ: The genetics of hypertrophic cardiomyopathy: Teare redux. Heart 2008, 94:1264–1268.CrossRefPubMedGoogle Scholar
  23. 23.
    Towbin JA, Bowles NE: Molecular genetics of left ventricular dysfunction. Curr Mol Med 2001, 1:81–90.CrossRefPubMedGoogle Scholar
  24. 24.
    Pasotti M, Klersy C, Pilotto A, et al.: Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol 2008, 52:1250–1260.CrossRefPubMedGoogle Scholar
  25. 25.
    Bowles NE, Bowles KR, Towbin JA: The “final common pathway” hypothesis and inherited cardiovascular disease. The role of cytoskeletal proteins in dilated cardiomyopathy. Herz 2000, 25:168–175.CrossRefPubMedGoogle Scholar
  26. 26.
    Hershberger RE, Parks SB, Kushner JD, et al.: Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy. Clin Transl Sci 2008, 1:21–26.CrossRefPubMedGoogle Scholar
  27. 27.
    Carniel E, Taylor MR, Sinagra G, et al.: Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy. Circulation 2005, 112:54–59.CrossRefPubMedGoogle Scholar
  28. 28.
    Rajan S, Ahmed RP, Jagatheesan G, et al.: Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity. Circ Res 2007, 101:205–214.CrossRefPubMedGoogle Scholar
  29. 29.
    McNair WP, Ku L, Taylor MR, et al.; Familial Cardiomyopathy Registry Research Group: SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation 2004, 110:2163–2167.CrossRefPubMedGoogle Scholar
  30. 30.
    Makita N: Phenotypic overlap of cardiac sodium channelopathies. Circ J 2009, 73:810–817.CrossRefPubMedGoogle Scholar
  31. 31.
    Fatkin D, MacRae C, Sasaki T, 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 1999, 341:1715–1724.CrossRefPubMedGoogle Scholar
  32. 32.
    Wolf CM, Wang L, Alcalai R, et al.: Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease. J Mol Cell Cardiol 2008, 44:293–303.CrossRefPubMedGoogle Scholar
  33. 33.
    Taylor MR, Fain PR, Sinagra G, et al.; Familial Dilated Cardiomyopathy Registry Research Group: Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol 2003, 41:771–780.CrossRefPubMedGoogle Scholar
  34. 34.
    Katritsis D, Wilmshurst PT, Wendon JA, et al.: Primary restrictive cardiomyopathy: clinical and pathologic characteristics. J Am Coll Cardiol 1991, 18:1230–1235.PubMedGoogle Scholar
  35. 35.
    Rivenes SM, Kearney DL, Smith EO, et al.: Sudden death and cardiovascular collapse in children with restrictive cardiomyopathy. Circulation 2000, 102:876–882.PubMedGoogle Scholar
  36. 36.
    Morita H, Rehm HL, Menesses A, et al.: Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med 2008, 358:1899–1908.CrossRefPubMedGoogle Scholar
  37. 37.
    Mogensen J, Murphy RT, Kubo T, et al.: Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy. J Am Coll Cardiol 2004, 44:2315–2325.CrossRefPubMedGoogle Scholar
  38. 38.
    Piñol-Ripoll G, Shatunov A, Cabello A, et al.: Severe infantileonset cardiomyopathy associated with a homozygous deletion in desmin. Neuromuscul Disord 2009, 19:418–422.CrossRefPubMedGoogle Scholar
  39. 39.
    Awad MM, Calkins H, Judge DP: Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nat Clin Pract Cardiovasc Med 2008, 5:258–267.CrossRefPubMedGoogle Scholar
  40. 40.
    Sen-Chowdhry S, McKenna WJ: Sudden cardiac death in the young: a strategy for prevention by targeted evaluation. Cardiology 2006, 105:196–206.CrossRefPubMedGoogle Scholar
  41. 41.
    Coonar AS, Protonotarios N, Tsatsopoulou A, et al.: Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (Naxos disease) maps to 17q21. Circulation 1998, 97:2049–2058.PubMedGoogle Scholar
  42. 42.
    Syrris P, Ward D, Asimaki A, et al.: Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease. Eur Heart J 2007, 28:581–588.CrossRefPubMedGoogle Scholar
  43. 43.
    Asimaki A, Tandri H, Huang H, et al.: A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. N Engl J Med 2009, 360:1075–1084.CrossRefPubMedGoogle Scholar
  44. 44.
    Saffitz JE: Arrhythmogenic cardiomyopathy and abnormalities of cell-to-cell coupling. Heart Rhythm 6(8 Suppl):S62–S65.Google Scholar
  45. 45.
    Sen-Chowdhry S, Syrris P, McKenna WJ: Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol 2007, 50:1813–1821.CrossRefPubMedGoogle Scholar
  46. 46.
    Dalal D, Molin LH, Piccini J, et al.: Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2. Circulation 2006, 113:1641–1649.CrossRefPubMedGoogle Scholar
  47. 47.
    Calkins H, Marcus F: Arrhythmogenic right ventricular cardiomyopathy/dysplasia: an update. Curr Cardiol Rep 2008, 10:367–375.CrossRefPubMedGoogle Scholar
  48. 48.
    Maron BJ, Towbin JA, Thiene G, et al.: American Heart Association; Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; Council on Epidemiology and Prevention: Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006, 113:1807–1816.CrossRefPubMedGoogle Scholar
  49. 49.
    Burke A, Mont E, Kutys R, Virmani R: Left ventricular noncompaction: a pathological study of 14 cases. Hum Pathol 2005, 36:403–411.CrossRefPubMedGoogle Scholar
  50. 50.
    Petersen SE, Selvanayagam JB, Wiesmann F, et al.: Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging. J Am Coll Cardiol 2005, 46:101–105.CrossRefPubMedGoogle Scholar
  51. 51.
    Ritter M, Oechslin E, Sütsch G, et al.: Isolated noncompaction of the myocardium in adults. Mayo Clin Proc 1997, 72:26–31.CrossRefPubMedGoogle Scholar
  52. 52.
    Jenni R, Oechslin EN, van der Loo B: Isolated ventricular non-compaction of the myocardium in adults. Heart 2007, 93:11–15.CrossRefPubMedGoogle Scholar
  53. 53.
    Kohli SK, Pantazis AA, Shah JS, et al.: Diagnosis of left-ventricular non-compaction in patients with left-ventricular systolic dysfunction: time for a reappraisal of diagnostic criteria? Eur Heart J 2008, 29:89–95.CrossRefPubMedGoogle Scholar
  54. 54.
    Oechslin EN, Attenhofer Jost CH, et al.: Long-term follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis. J Am Coll Cardiol 2000, 36:493–500.CrossRefPubMedGoogle Scholar
  55. 55.
    Garnier A, Girod G: Cardiac re-synchronization therapy in a patient with isolated ventricular non-compaction: a case report. Eur J Echocardiogr 2009, 10:713–715.CrossRefPubMedGoogle Scholar
  56. 56.
    Sasse-Klaassen S, Gerull B, Oechslin E, et al.: Isolated noncompaction of the left ventricular myocardium in the adult is an autosomal dominant disorder in the majority of patients. Am J Med Genet A 2003, 119A:162–167.CrossRefPubMedGoogle Scholar
  57. 57.
    Ichida F: Left ventricular noncompaction. Circ J 2009, 73:19–26.CrossRefPubMedGoogle Scholar
  58. 58.
    Grady RM, Grange RW, Lau KS, et al.: Role for alpha-dystrobrevin in the pathogenesis of dystrophin-dependent muscular dystrophies. Nat Cell Biol 1999, 1:215–220.CrossRefPubMedGoogle Scholar
  59. 59.
    Klaassen, S., et al.: Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation 2008, 117:2893–2901.CrossRefPubMedGoogle Scholar
  60. 60.
    Shan L, Makita N, Xing Y, et al.: SCN5A variants in Japanese patients with left ventricular noncompaction and arrhythmia. Mol Genet Metab 2008, 93:468–474.CrossRefPubMedGoogle Scholar
  61. 61.
    Priori SG, Napolitano C, Humphries SE, Skipworth J: Genetics of cardiovascular diseases. In The ESC Textbook of Cardiovascular Medicine. Edited by Camm JA, Lüscher TF, Serruys PW. New York: Oxford University Press; 2009:281–312.Google Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  • Steven J. Fowler
  • Carlo Napolitano
  • Silvia G. Priori
    • 1
  1. 1.Leon H. Carney Division of CardiologyNew York University Langone Medical CenterNew YorkUSA

Personalised recommendations