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Evolving Approaches to Genetic Evaluation of Specific Cardiomyopathies

  • Biomarkers of Heart Failure (W H W Tang, Section Editor)
  • Published:
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Abstract

The understanding of the genetic basis of cardiomyopathy has expanded significantly over the past 2 decades. The increasing availability, shortening diagnostic time, and lowering costs of genetic testing have provided researchers and physicians with the opportunity to identify the underlying genetic determinants for thousands of genetic disorders, including inherited cardiomyopathies, in effort to improve patient morbidities and mortality. As such, genetic testing has advanced from basic scientific research to clinical application and has been incorporated as part of patient evaluations for suspected inherited cardiomyopathies. Genetic evaluation framework of inherited cardiomyopathies typically encompasses careful evaluation of family history, genetic counseling, clinical screening of family members, and if appropriate, molecular genetic testing. This review summarizes the genetics, current guideline recommendations, and evidence supporting the genetic evaluation framework of five hereditary forms of cardiomyopathy: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM), and left ventricular noncompaction (LVNC).

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Maron BJ, Towbin JA, Thiene G, et al. 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;113:1807–16.

    Article  PubMed  Google Scholar 

  2. Maisch B, Noutsias M, Ruppert V, et al. Cardiomyopathies: classification, diagnosis and treatment. Heart Fail Clin. 2012;8(1):53–78.

    Article  PubMed  Google Scholar 

  3. Cahill TJ, Ashrafian H, Watkins H. Genetic cardiomyopathies causing heart failure. Circ Res. 2013;113(6):660–75.

    Article  CAS  PubMed  Google Scholar 

  4. Watkins H, Ashrafian H, Redwood C. Inherited cardiomyopathies. N Engl J Med. 2011;364:1643–56.

    Article  CAS  PubMed  Google Scholar 

  5. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011;8(8):1308–39. Official practice guidelines outlining important considerations for genetic evaluation of channelopathies and inherited arrhythmias.

    Article  PubMed  Google Scholar 

  6. Hershberger RE, Lindenfeld J, Mestroni L, et al. Genetic evaluation of cardiomyopathy--a Heart Failure Society of America practice guideline. J Card Fail. 2009;15(2):83–97. Official practice guidelines from the Heart Failure Society of America, outlining important considerations for genetic evaluation of cardiomyopathies.

    Article  PubMed  Google Scholar 

  7. Charron P, Arad M, Arbustini E, Basso C, et al. Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31(22):2715–26.

    Article  PubMed  Google Scholar 

  8. Mestroni L, Maisch B, McKenna WJ, et al. Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy. Eur Heart J. 1999;20(2):93–102.

    Article  CAS  PubMed  Google Scholar 

  9. Hershberger RE, Siegfried JD. Update 2011: clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol. 2011;57(16):1641–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Michels VV, Moll PP, Miller FA, et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med. 1992;326:77–82.

    Article  CAS  PubMed  Google Scholar 

  11. Grunig E, Tasman JA, Kucherer H, et al. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol. 1998;31:186–94.

    Article  CAS  PubMed  Google Scholar 

  12. Baig MK, Goldman JH, Caforio AP, et al. Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives and may represent early disease. J Am Coll Cardiol. 1998;31:195–201.

    Article  CAS  PubMed  Google Scholar 

  13. Towbin JA, Bowles NE. The failing heart. Nature. 2002;415(6868):227–33.

    Article  CAS  PubMed  Google Scholar 

  14. Teekakirikul P, Kelly MA, Rehm HL, et al. Inherited cardiomyopathies: molecular genetics and clinical genetic testing in the postgenomic era. J Mol Diagn. 2013;15(2):158–70.

    Article  PubMed  Google Scholar 

  15. Towbin JA. Inherited cardiomyopathies. Circ J. 2014;78(10):2347–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Dellefave L, McNally EM. The genetics of dilated cardiomyopathy. Curr Opin Cardiol. 2010;25(3):198–204.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Schuster SC. Next-generation sequencing transforms today's biology. Nat Methods. 2008;5(1):16–8.

    Article  CAS  PubMed  Google Scholar 

  18. Hall N. Advanced sequencing technologies and their wider impact in microbiology. J Exp Biol. 2007;210(Pt 9):1518–25.

    Article  CAS  PubMed  Google Scholar 

  19. GeneTests. http://www.genetests.org.

  20. National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/gtr/.

  21. Burkett EL, Hershberger RE. Clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol. 2005;45:969–81.

    Article  CAS  PubMed  Google Scholar 

  22. Hershberger RE. Cardiovascular genetic medicine: evolving concepts, rationale, and implementation. J Cardiovasc Transl Res. 2008;1(2):137–43.

    Article  PubMed  Google Scholar 

  23. Parks SB, Kushner JD, Nauman D, et al. Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. Am Heart J. 2008;156:161e169.

    Article  Google Scholar 

  24. McNair WP, Ku L, Taylor MR, et al. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation. 2004;110:2163e7.

    Article  Google Scholar 

  25. van Spaendonck-Zwarts KY, van Hessem L, Jongbloed JD, et al. Desmin-related myopathy. Clin Genet. 2011;80(4):354–66.

    Article  PubMed  Google Scholar 

  26. van Berlo JH, de Voogt WG, van der Kooi AJ, et al. Metaanalysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? J Mol Med. 2005;83:79–83.

    Article  CAS  PubMed  Google Scholar 

  27. Meune C, Van Berlo JH, Anselme F, et al. Primary prevention of sudden death in patients with lamin A/C gene mutations. N Engl J Med. 2006;354:209–10.

    Article  CAS  PubMed  Google Scholar 

  28. Herman DS, Lam L, Taylor MR, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012;366(7):619–28.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. 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(4):785–9.

    Article  CAS  PubMed  Google Scholar 

  30. Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol. 2009;54(3):201–11.

    Article  CAS  PubMed  Google Scholar 

  31. Seidman CE, Seidman JG. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history. Circ Res. 2011;108(6):743–50.

    Article  CAS  PubMed  Google Scholar 

  32. Roma-Rodrigues C, Fernandes AR. Genetics of hypertrophic cardiomyopathy: advances and pitfalls in molecular diagnosis and therapy. Appl Clin Genet. 2014;7:195–208.

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Richard P, Charron P, Carrier L, et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003;107(17):2227–32.

    Article  PubMed  Google Scholar 

  34. Watkins H, Thierfelder L, Hwang DS, et al. Sporadic hypertrophic cardiomyopathy due to de novo myosin mutations. J Clin Invest. 1992;90(5):1666–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Ingles J, Doolan A, Chiu C, Seidman J, et al. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. J Med Genet. 2005;42, e59.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124(24):e783–831.

    Article  PubMed  Google Scholar 

  37. Jarcho JA, McKenna WJ, Pare JA, et al. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. N Engl J Med. 1989;321:1372–8.

    Article  CAS  PubMed  Google Scholar 

  38. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol. 2012;60:705–15.

    Article  PubMed  Google Scholar 

  39. Olivotto I, Girolami F, Ackerman MJ, et al. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc. 2008;83(6):630–8.

    Article  CAS  PubMed  Google Scholar 

  40. Wordsworth S, Leal J, Blair E, et al. DNA testing for hypertrophic cardiomyopathy: a cost-effectiveness model. Eur Heart J. 2010;31:926–35.

    Article  PubMed  Google Scholar 

  41. Basso C, Corrado D, Marcus FI, et al. Arrhythmogenic right ventricular cardiomyopathy. Lancet. 2009;373:1289–300.

    Article  PubMed  Google Scholar 

  42. Gemayel C, Pelliccia A, Thompson PD. Arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2001;38:1773.

    Article  CAS  PubMed  Google Scholar 

  43. Bauce B, Frigo G, Marcus FI, et al. Comparison of clinical features of arrhythmogenic right ventricular cardiomyopathy in men versus women. Am J Cardiol. 2008;102:1252e1257.

    Article  Google Scholar 

  44. Iyer VR, Chin AJ. Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). Am J Med Genet Part C Semin Med Genet. 2013;163C:185–97.

    Article  PubMed  Google Scholar 

  45. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation. 2010;121:1533–41.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Murray B. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C): a review of molecular and clinical literature. J Genet Counsel. 2012;21:497–504.

    Article  Google Scholar 

  47. Quarta G, Muir A, Pantazis A, et al. Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. Circulation. 2011;123(23):2701–9.

    Article  PubMed  Google Scholar 

  48. Smith W. Members of CSANZ Cardiovascular Genetics Working Group. Guidelines for the diagnosis and management of arrhythmogenic right ventricular cardiomyopathy. Heart Lung Circ. 2011;20(12):757–60.

    Article  PubMed  Google Scholar 

  49. Bauce B, Basso C, Rampazzo A, et al. Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations. Eur Heart J. 2005;26:1666–75.

    Article  CAS  PubMed  Google Scholar 

  50. Dalal D, Molin LH, Piccini J, et al. Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2. Circulation. 2006;113:1641–9.

    Article  CAS  PubMed  Google Scholar 

  51. Marcus FI, Edson S, Towbin JA. Genetics of arrhythmogenic right ventricular cardiomyopathy: a practical guide for physicians. J Am Coll Cardiol. 2013;61(19):1945–8.

    Article  PubMed  Google Scholar 

  52. Kapplinger JD, Landstrom AP, Salisbury BA, et al. Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. J Am Coll Cardiol. 2011;57:2317–27.

    Article  CAS  PubMed  Google Scholar 

  53. Sen-Chowdhry S, Syrris P, McKenna WJ. Genetics of restrictive cardiomyopathy. Heart Fail Clin. 2010;6(2):179–86.

    Article  PubMed  Google Scholar 

  54. Peled Y, Gramlich M, Yoskovitz G, et al. Titin mutation in familial restrictive cardiomyopathy. Int J Cardiol. 2014;171(1):24–30.

    Article  PubMed  Google Scholar 

  55. Caleshu C, Sakhuja R, Nussbaum RL, et al. Furthering the link between the sarcomere and primary cardiomyopathies: restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy. Am J Med Genet A. 2011;155A(9):2229–35.

    Article  PubMed  Google Scholar 

  56. Alfares AA, Kelly MA, McDermott G, et al. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015. doi:10.1038/gim.2014.205.

    PubMed  Google Scholar 

  57. Huby AC, Mendsaikhan U, Takagi K, et al. Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy. J Am Coll Cardiol. 2014;64(25):2765–76.

    Article  CAS  PubMed  Google Scholar 

  58. Oechslin E, Jenni R. Left ventricular non-compaction revisited: a distinct phenotype with genetic heterogeneity? Eur Heart J. 2011;32(12):1446–56.

    Article  PubMed  Google Scholar 

  59. Carrilho-Ferreira P, Almeida AG, Pinto FJ. Non-compaction cardiomyopathy: prevalence, prognosis, pathoetiology, genetics, and risk of cardioembolism. Curr Heart Fail Rep. 2014;11(4):393–403.

    Article  CAS  PubMed  Google Scholar 

  60. Weiford BC, Subbarao VD, Mulhern KM. Noncompaction of the ventricular myocardium. Circulation. 2004;109:2965.

    Article  PubMed  Google Scholar 

  61. Sen-Chowdhry S, McKenna WJ. Left ventricular noncompaction and cardiomyopathy: cause, contributor, or epiphenomenon? Curr Opin Cardiol. 2008;23:171–5.

    Article  PubMed  Google Scholar 

  62. Hoedemaekers YM, Caliskan K, Michels M, et al. The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. Circ Cardiovasc Genet. 2010;3(3):232–9.

    Article  PubMed  Google Scholar 

  63. Klaassen S, Probst S, Oechslin E, et al. Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation. 2008;117:2893–901.

    Article  CAS  PubMed  Google Scholar 

  64. Ho CY, Lakdawala NK, Cirino AL, et al. Diltiazem treatment for pre-clinical hypertrophic cardiomyopathy sarcomere mutation carriers: a pilot randomized trial to modify disease expression. JACC Heart Fail. 2015;3(2):180–8.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Kaufman Center for Heart Failure, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA

    Loon Yee Louis Teo & W. H. Wilson Tang

  2. Division of Genetics and Genomics, MetroHealth Medical Center, Cleveland, OH, 44109, USA

    Rocio T. Moran

  3. Center for Clinical Genomics, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH, 44195, USA

    W. H. Wilson Tang

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  1. Loon Yee Louis Teo
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  2. Rocio T. Moran
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Correspondence to W. H. Wilson Tang.

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Loon Yee Louis Teo and Rocio T. Moran declare that they have no conflict of interest.

W. H. Wilson Tang declares grants from the National Institutes of Health during the conduct of this study.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Biomarkers of Heart Failure

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Teo, L.Y.L., Moran, R.T. & Tang, W.H.W. Evolving Approaches to Genetic Evaluation of Specific Cardiomyopathies. Curr Heart Fail Rep 12, 339–349 (2015). https://doi.org/10.1007/s11897-015-0271-7

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