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Genetic Testing in the Contemporary Diagnosis of Cardiomyopathy

  • Nonpharmacologic Therapy: Surgery, Ventricular Assist Devices, Biventricular Pacing, and Exercise (AK Hasan, Section Editor)
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Abstract

The heritable cardiomyopathies are relatively common conditions that can lead to heart failure and sudden cardiac death. Family history collection, genetic testing and genetic counseling are recommended for these patients and families in multiple practice guidelines and consensus statements. Research discoveries and rapidly dropping costs of DNA sequencing technologies have resulted in the availability of multiple cardiomyopathy genetic testing panels. Genetic testing not only helps in determining the underlying etiology of idiopathic and familial cardiomyopathies, but is also a powerful tool in the determination of which relatives are at-risk and which are not. Both pre- and post-test genetic counseling is an imperative component of genetic testing, as there are many benefits and limitations of genetic testing that need discussed with each patient undergoing this process.

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References

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

  1. •• Hershberger RE, et al. Genetic evaluation of cardiomyopathy--a Heart Failure Society of America practice guideline. J Card Fail. 2009;15(2):83–97. This oft-cited practice guideline is the mainstay of genetic testing and clinical screening recommendations for the inherited cardiomyopathies..

    Article  PubMed  Google Scholar 

  2. Charron P, 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 

  3. •• Ackerman MJ, 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). Hear Rhythm. 2011;8(8):1308–39. This is another important expert statement regarding genetic testing for inherited cardiomyopathies..

    Article  Google Scholar 

  4. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol. 2012;60(8):705–15.

    Article  PubMed  Google Scholar 

  5. Marian AJ. Phenotypic plasticity of sarcomeric protein mutations. J Am Coll Cardiol. 2007;49(25):2427–9.

    Article  PubMed  CAS  Google Scholar 

  6. Fowler SJ, Napolitano C, Priori SG. The genetics of cardiomyopathy: genotyping and genetic counseling. Curr Treat Options Cardiovasc Med. 2009;11(6):433–46.

    Article  PubMed  Google Scholar 

  7. Klaassen S, et al. Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation. 2008;117(22):2893–901.

    Article  PubMed  CAS  Google Scholar 

  8. Kubo T, et al. Prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy with restrictive phenotype. J Am Coll Cardiol. 2007;49(25):2419–26.

    Article  PubMed  CAS  Google Scholar 

  9. Satoh M, et al. Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem Biophys Res Commun. 1999;262(2):411–7.

    Article  PubMed  CAS  Google Scholar 

  10. •• Herman DS, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012;366(7):619–28. This highly impactful study showed that truncating mutations of the gene TTN are implicated in approximately 25 % of familial DCM and in 18 % of sporadic cases, which has important implications for clinical genetic testing for this condition..

    Article  PubMed  CAS  Google Scholar 

  11. Greaser ML. Stressing the giant: a new approach to understanding dilated cardiomyopathy. J Mol Cell Cardiol. 2009;47(3):347–9.

    Article  PubMed  CAS  Google Scholar 

  12. Taylor M, et al. Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Circulation. 2011;124(8):876–85.

    Article  PubMed  Google Scholar 

  13. Hershberger RE, et al. Progress with genetic cardiomyopathies: screening, counseling, and testing in dilated, hypertrophic, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Heart Fail. 2009;2(3):253–61.

    Article  PubMed  Google Scholar 

  14. Judge DP. Use of genetics in the clinical evaluation of cardiomyopathy. JAMA. 2009;302(22):2471–6.

    Article  PubMed  CAS  Google Scholar 

  15. Wheeler M, et al. A new era in clinical genetic testing for hypertrophic cardiomyopathy. J Cardiovasc Transl Res. 2009;2(4):381–91.

    Article  PubMed  Google Scholar 

  16. Maron BJ, 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  PubMed  CAS  Google Scholar 

  17. Maron BJ. Sudden death in young athletes. N Engl J Med. 2003;349(11):1064–75.

    Article  PubMed  CAS  Google Scholar 

  18. Konno T, et al. Genetics of hypertrophic cardiomyopathy. Curr Opin Cardiol. 2010;25(3):205–9.

    Article  PubMed  Google Scholar 

  19. Charron P, et al. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene. Circulation. 1998;97(22):2230–6.

    Article  PubMed  CAS  Google Scholar 

  20. Niimura H, et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med. 1998;338(18):1248–57.

    Article  PubMed  CAS  Google Scholar 

  21. Page SP, et al. Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome. Circ Cardiovasc Genet. 2012;5(2):156–66.

    Article  PubMed  CAS  Google Scholar 

  22. Makhoul M, et al. Clinical spectrum in a family with tropomyosin-mediated hypertrophic cardiomyopathy and sudden death in childhood. Pediatr Cardiol. 2011;32(2):215–20.

    Article  PubMed  Google Scholar 

  23. Hershberger RE, Morales A, Siegfried JD. Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals. Genet Med. 2010;12(11):655–67.

    Article  PubMed  CAS  Google Scholar 

  24. Grunig E, et al. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol. 1998;31(1):186–94.

    Article  PubMed  CAS  Google Scholar 

  25. Michels VV, et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med. 1992;326(2):77–82.

    Article  PubMed  CAS  Google Scholar 

  26. Burkett EL, Hershberger RE. Clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol. 2005;45(7):969–81.

    Article  PubMed  CAS  Google Scholar 

  27. 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  CAS  Google Scholar 

  28. Sen-Chowdhry S, et al. Arrhythmogenic cardiomyopathy: etiology, diagnosis, and treatment. Annu Rev Med. 2010;61:233–53.

    Article  PubMed  CAS  Google Scholar 

  29. Marcus FI, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J. 2010;31(7):806–14.

    Article  PubMed  Google Scholar 

  30. Sen-Chowdhry S, et al. Left-dominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity. J Am Coll Cardiol. 2008;52(25):2175–87.

    Article  PubMed  Google Scholar 

  31. Quarta G, 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 

  32. Xu T, et al. Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2010;55(6):587–97.

    Article  PubMed  CAS  Google Scholar 

  33. Sen-Chowdhry S, et al. Mutational heterogeneity, modifier genes, and environmental influences contribute to phenotypic diversity of arrhythmogenic cardiomyopathy. Circ Cardiovasc Genet. 2010;3(4):323–30.

    Article  PubMed  Google Scholar 

  34. Maron BJ, 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(14):1807–16.

    Article  PubMed  Google Scholar 

  35. Zaragoza MV, Arbustini E, Narula J. Noncompaction of the left ventricle: primary cardiomyopathy with an elusive genetic etiology. Curr Opin Pediatr. 2007;19(6):619–27.

    Article  PubMed  Google Scholar 

  36. Bleyl SB, et al. Neonatal, lethal noncompaction of the left ventricular myocardium is allelic with Barth syndrome. Am J Hum Genet. 1997;61(4):868–72.

    Article  PubMed  CAS  Google Scholar 

  37. Hoedemaekers YM, 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 

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

    Article  PubMed  Google Scholar 

  39. Fitzpatrick AP, et al. Familial restrictive cardiomyopathy with atrioventricular block and skeletal myopathy. Br Heart J. 1990;63(2):114–8.

    Article  PubMed  CAS  Google Scholar 

  40. Mogensen J, et al. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest. 2003;111(2):209–16.

    PubMed  CAS  Google Scholar 

  41. Caleshu C, 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.

    PubMed  Google Scholar 

  42. Ware SM, et al. Pediatric restrictive cardiomyopathy associated with a mutation in beta-myosin heavy chain. Clin Genet. 2008;73(2):165–70.

    Article  PubMed  CAS  Google Scholar 

  43. Kaski JP, et al. Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes. Heart. 2008;94(11):1478–84.

    Article  PubMed  CAS  Google Scholar 

  44. Meder B, et al. Targeted next-generation sequencing for the molecular genetic diagnostics of cardiomyopathies. Circ Cardiovasc Genet. 2011;4(2):110–22.

    Article  PubMed  CAS  Google Scholar 

  45. Van Driest SL, et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004;44(9):1903–10.

    Article  PubMed  Google Scholar 

  46. Richard P, 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 

  47. Girolami F, et al. Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. J Am Coll Cardiol. 2010;55(14):1444–53.

    Article  PubMed  CAS  Google Scholar 

  48. Ashley EA, et al. Genetics and cardiovascular disease: a policy statement from the American Heart Association. Circulation. 2012;126(1):142–57.

    Article  PubMed  Google Scholar 

  49. Caleshu C, et al. Use and interpretation of genetic tests in cardiovascular genetics. Heart. 2010;96(20):1669–75.

    Article  PubMed  Google Scholar 

  50. Washington, U.o. GeneTests. [cited 2012 9/10/12]; Available from: genetests.org.

  51. National Center for Biotechnology Information, U.S.N.L.o.M. Genetic Testing Registry. 2012 [cited 2012 9/10/12]; Available from: http://www.ncbi.nlm.nih.gov/gtr/.

  52. • Ingles J, et al. A cost-effectiveness model of genetic testing for the evaluation of families with hypertrophic cardiomyopathy. Heart. 2012;98(8):625–30. This study shows that predictive genetic testing is highly cost-effective in HCM families compared to clinical screening alone..

    Article  PubMed  Google Scholar 

  53. Lakdawala NK, et al. Genetic testing for dilated cardiomyopathy in clinical practice. J Card Fail. 2012;18(4):296–303.

    Article  PubMed  Google Scholar 

  54. Ho CY. Hypertrophic cardiomyopathy in 2012. Circulation. 2012;125(11):1432–8.

    Article  PubMed  Google Scholar 

  55. A map of human genome variation from population-scale sequencing. Nature. 2010;467(7319):1061–73. http://www.ncbi.nlm.nih.gov/pubmed/20981092.

  56. Tennessen JA, et al. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science. 2012;337(6090):64–9.

    Article  PubMed  CAS  Google Scholar 

  57. • Golbus JR, et al. Population-based variation in cardiomyopathy genes. Circ Cardiovasc Genet. 2012;5(4):391–9. By querying the 1000 Genomes Project database, this study showed that the frequency of predicted pathogenic variants in genes associated with cardiomyopathies was higher than expected based on known cardiomyopathy prevalence data..

    Article  PubMed  Google Scholar 

  58. Kapplinger JD, et al. Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. J Am Coll Cardiol. 2011;57(23):2317–27.

    Article  PubMed  CAS  Google Scholar 

  59. Resta R, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns. 2006;15(2):77–83.

    Article  PubMed  Google Scholar 

  60. Cowan J, et al. Genetic testing and genetic counseling in cardiovascular genetic medicine: overview and preliminary recommendations. Congest Heart Fail. 2008;14(2):97–105.

    Article  PubMed  Google Scholar 

  61. Gersh BJ, 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. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;58(25):e212–60.

    Article  PubMed  CAS  Google Scholar 

  62. Morales A, et al. Family history: an essential tool for cardiovascular genetic medicine. Congest Heart Fail. 2008;14(1):37–45.

    Article  PubMed  Google Scholar 

  63. Kuliev A, et al. PGD for inherited cardiac diseases. Reprod Biomed Online. 2012;24(4):443–53.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  65. • Aatre RD, Day SM. Psychological issues in genetic testing for inherited cardiovascular diseases. Circ Cardiovasc Genet. 2011;4(1):81–90. This is an outstanding review of the issues patients face from a psychological standpoint when undergoing genetic testing for heritable heart diseases..

    Article  PubMed  Google Scholar 

  66. van der Roest WP, et al. Family letters are an effective way to inform relatives about inherited cardiac disease. Am J Med Genet A. 2009;149A(3):357–63.

    Article  PubMed  Google Scholar 

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Sturm, A.C. Genetic Testing in the Contemporary Diagnosis of Cardiomyopathy. Curr Heart Fail Rep 10, 63–72 (2013). https://doi.org/10.1007/s11897-012-0124-6

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