UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Genetics of dilated cardiomyopathy

Author
Ray E Hershberger, MD
Section Editors
William J McKenna, MD
Benjamin A Raby, MD, MPH
Deputy Editor
Susan B Yeon, MD, JD, FACC

INTRODUCTION

Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and is the most common diagnosis in patients referred for cardiac transplantation. DCM is characterized by dilatation and systolic dysfunction of one or both ventricles. (See "Definition and classification of the cardiomyopathies".)

DCM is classified as idiopathic (idiopathic dilated cardiomyopathy, or IDC) when all recognized causes have been excluded. Potentially diagnosable causes of DCM include a variety of toxic, metabolic, or infectious agents. (See "Causes of dilated cardiomyopathy".) Ischemic heart disease must also be excluded. Although specialists commonly apply the diagnosis of IDC to DCMs of unknown cause, an etiology is present but undetected.

Family-based studies of first-degree relatives during the past few decades have established that familial dilated cardiomyopathy (known as familial DCM, or FDC) can be identified in 20 to 35 percent of patients diagnosed with IDC by clinical screening of family members. Most familial DCM is transmitted in an autosomal dominant inheritance pattern, although all inheritance patterns have been identified (autosomal recessive, X-linked, and mitochondrial). During the past 20 years, familial DCM genetic studies have identified mutations in more than 30 genes.

Most patients with genetic DCM will have an initial diagnosis of IDC. Given the frequency of familial DCM, evaluation of new IDC cases should include a careful three to four generation family history and clinical screening of first-degree family members as described below.

Developments have dramatically and favorably affected efforts to identify and understand the genetic basis of DCM, including the enormous impact of next generation sequencing (NGS), and the availability of very large databases of exome or genome sequences that can be used as reference sequences in gene discovery programs (eg, the Exome Study Project, Exome Variant Server, the Thousand Genomes Project, and the ExAC database). Extensive discovery studies over the past 20 years have identified rare variants in numerous genes.

                     

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Mon May 23 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol 2013; 10:531.
  2. Haas J, Frese KS, Peil B, et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J 2015; 36:1123.
  3. Mestroni L, Rocco C, Gregori D, et al. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group. J Am Coll Cardiol 1999; 34:181.
  4. http://www.ncbi.nlm.nih.gov/gtr/.
  5. www.ncbi.nlm.nih.gov/sites/GeneTests/review/disease/dilated%20cardiomyopathy?db=genetests&search_param=contains/ (Accessed on August 31, 2009).
  6. www.genetests.org.
  7. Kamisago M, Sharma SD, DePalma SR, et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 2000; 343:1688.
  8. Olson TM, Kishimoto NY, Whitby FG, Michels VV. Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy. J Mol Cell Cardiol 2001; 33:723.
  9. Li D, Czernuszewicz GZ, Gonzalez O, et al. Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. Circulation 2001; 104:2188.
  10. Mogensen J, Murphy RT, Shaw T, et al. Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2004; 44:2033.
  11. 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.
  12. Herman DS, Lam L, Taylor MR, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med 2012; 366:619.
  13. Norton N, Li D, Rampersaud E, et al. Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy. Circ Cardiovasc Genet 2013; 6:144.
  14. Morales A, Pinto JR, Siegfried JD, et al. Late onset sporadic dilated cardiomyopathy caused by a cardiac troponin T mutation. Clin Transl Sci 2010; 3:219.
  15. Knöll R, Postel R, Wang J, et al. Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells. Circulation 2007; 116:515.
  16. Moiseyeva EP, Weller PA, Zhidkova NI, et al. Organization of the human gene encoding the cytoskeletal protein vinculin and the sequence of the vinculin promoter. J Biol Chem 1993; 268:4318.
  17. Maeda M, Holder E, Lowes B, et al. Dilated cardiomyopathy associated with deficiency of the cytoskeletal protein metavinculin. Circulation 1997; 95:17.
  18. Olson TM, Illenberger S, Kishimoto NY, et al. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation 2002; 105:431.
  19. Bienengraeber M, Olson TM, Selivanov VA, et al. ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating. Nat Genet 2004; 36:382.
  20. 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; 156:161.
  21. 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.
  22. Brodsky GL, Muntoni F, Miocic S, et al. Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement. Circulation 2000; 101:473.
  23. Arbustini E, Pilotto A, Repetto A, et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J Am Coll Cardiol 2002; 39:981.
  24. Taylor MR, Fain PR, Sinagra G, et al. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol 2003; 41:771.
  25. van Tintelen JP, Tio RA, Kerstjens-Frederikse WS, et al. Severe myocardial fibrosis caused by a deletion of the 5' end of the lamin A/C gene. J Am Coll Cardiol 2007; 49:2430.
  26. Kass S, MacRae C, Graber HL, et al. A gene defect that causes conduction system disease and dilated cardiomyopathy maps to chromosome 1p1-1q1. Nat Genet 1994; 7:546.
  27. MacLeod HM, Culley MR, Huber JM, McNally EM. Lamin A/C truncation in dilated cardiomyopathy with conduction disease. BMC Med Genet 2003; 4:4.
  28. Pasotti M, Klersy C, Pilotto A, et al. Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol 2008; 52:1250.
  29. Olson TM, Keating MT. Mapping a cardiomyopathy locus to chromosome 3p22-p25. J Clin Invest 1996; 97:528.
  30. McNair WP, Ku L, Taylor MR, et al. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation 2004; 110:2163.
  31. Olson TM, Michels VV, Ballew JD, et al. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA 2005; 293:447.
  32. van Spaendonck-Zwarts KY, van Tintelen JP, van Veldhuisen DJ, et al. Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy. Circulation 2010; 121:2169.
  33. Morales A, Painter T, Li R, et al. Rare variant mutations in pregnancy-associated or peripartum cardiomyopathy. Circulation 2010; 121:2176.
  34. van Spaendonck-Zwarts KY, Posafalvi A, van den Berg MP, et al. Titin gene mutations are common in families with both peripartum cardiomyopathy and dilated cardiomyopathy. Eur Heart J 2014; 35:2165.
  35. Ware JS, Li J, Mazaika E, et al. Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies. N Engl J Med 2016; 374:233.
  36. Grünig E, Tasman JA, Kücherer H, et al. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol 1998; 31:186.
  37. Gavazzi A, Repetto A, Scelsi L, et al. Evidence-based diagnosis of familial non-X-linked dilated cardiomyopathy. Prevalence, inheritance and characteristics. Eur Heart J 2001; 22:73.
  38. Olson TM, Thibodeau SN, Lundquist PA, et al. Exclusion of a primary gene defect at the HLA locus in familial idiopathic dilated cardiomyopathy. J Med Genet 1995; 32:876.
  39. Marriott JB, Goldman JH, Keeling PJ, et al. Abnormal cytokine profiles in patients with idiopathic dilated cardiomyopathy and their asymptomatic relatives. Heart 1996; 75:287.
  40. Muntoni F, Cau M, Ganau A, et al. Brief report: deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. N Engl J Med 1993; 329:921.
  41. Towbin JA, Hejtmancik JF, Brink P, et al. X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation 1993; 87:1854.
  42. Franz WM, Cremer M, Herrmann R, et al. X-linked dilated cardiomyopathy. Novel mutation of the dystrophin gene. Ann N Y Acad Sci 1995; 752:470.
  43. Ortiz-Lopez R, Li H, Su J, et al. Evidence for a dystrophin missense mutation as a cause of X-linked dilated cardiomyopathy. Circulation 1997; 95:2434.
  44. Franz WM, Müller M, Müller OJ, et al. Association of nonsense mutation of dystrophin gene with disruption of sarcoglycan complex in X-linked dilated cardiomyopathy. Lancet 2000; 355:1781.
  45. Bies RD, Maeda M, Roberds SL, et al. A 5' dystrophin duplication mutation causes membrane deficiency of alpha-dystroglycan in a family with X-linked cardiomyopathy. J Mol Cell Cardiol 1997; 29:3175.
  46. Muntoni F, Wilson L, Marrosu G, et al. A mutation in the dystrophin gene selectively affecting dystrophin expression in the heart. J Clin Invest 1995; 96:693.
  47. Nigro G, Politano L, Nigro V, et al. Mutation of dystrophin gene and cardiomyopathy. Neuromuscul Disord 1994; 4:371.
  48. Michels VV, Pastores GM, Moll PP, et al. Dystrophin analysis in idiopathic dilated cardiomyopathy. J Med Genet 1993; 30:955.
  49. Arbustini E, Diegoli M, Morbini P, et al. Prevalence and characteristics of dystrophin defects in adult male patients with dilated cardiomyopathy. J Am Coll Cardiol 2000; 35:1760.
  50. Marshall JD, Bronson RT, Collin GB, et al. New Alström syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med 2005; 165:675.
  51. Collin GB, Marshall JD, Ikeda A, et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome. Nat Genet 2002; 31:74.
  52. Hearn T, Renforth GL, Spalluto C, et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alström syndrome. Nat Genet 2002; 31:79.
  53. Murphy RT, Mogensen J, Shaw A, et al. Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy. Lancet 2004; 363:371.
  54. Santorelli FM, Mak SC, El-Schahawi 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 1996; 58:933.
  55. Schönberger J, Wang L, Shin JT, et al. Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. Nat Genet 2005; 37:418.
  56. Schönberger J, Levy H, Grünig E, et al. Dilated cardiomyopathy and sensorineural hearing loss: a heritable syndrome that maps to 6q23-24. Circulation 2000; 101:1812.
  57. Taylor MR, Slavov D, Ku L, et al. Prevalence of desmin mutations in dilated cardiomyopathy. Circulation 2007; 115:1244.
  58. Goldfarb LG, Vicart P, Goebel HH, Dalakas MC. Desmin myopathy. Brain 2004; 127:723.
  59. Goldfarb LG, Dalakas MC. Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease. J Clin Invest 2009; 119:1806.
  60. Hershberger RE, Lindenfeld J, Mestroni L, et al. Genetic evaluation of cardiomyopathy--a Heart Failure Society of America practice guideline. J Card Fail 2009; 15:83.
  61. 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). Europace 2011; 13:1077.
  62. Hershberger RE, Morales A, Siegfried JD. Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals. Genet Med 2010; 12:655.
  63. Morales A, Hershberger RE. The Rationale and Timing of Molecular Genetic Testing for Dilated Cardiomyopathy. Can J Cardiol 2015; 31:1309.