Korean Circulation Journal

The Korean Society of Cardiology (대한심장학회)
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Hereditary Dilated Cardiomyopathy: Recent Advances in Genetic Diagnostics

  • Park, Hyun-Young (Division of Cardiovascular and Rare Diseases, Center for Biomedical Science, Korea National Institute of Health)
  • Received : 2016.01.12
  • Accepted : 2016.11.11
  • Published : 2017.05.31
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Abstract

Dilated cardiomyopathy (DCM) is the most common cause of heart failure in young adults and up to 50% of idiopathic DCM is thought to be caused by genetic mutations in candidate genes. Although a genetic diagnosis can confirm a clinical diagnosis of hereditary DCM, genetic testing has not been easily accessible due to genetic heterogeneity and complexity. Next-generation sequencing (NGS) technologies have recently been introduced, and genetic testing for multiple genes is currently available and more than 40 different genes have been associated with DCM. In Korea, the government has supported genetic diagnosis for patients with idiopathic DCM. When a targeted gene panel with NGS technology was used, the detection rate was about 40%. MYBPC3, LMNA, and MYH7 were the most frequently identified genes, and the pattern of causative genes was different from previous reports. In the analysis, a significant number of subjects (42.0%) had rare or novel unspecified variants in DCM candidate genes, which should be assessed as potential causative mutations. Developing a more comprehensive test panel with additional DCM genes and whole exome sequencing will improve the detection rate, and allow genetic testing to be an option for patients with idiopathic DCM. However, all genetic variations are not pathogenic mutations, and the majority of reported mutations in DCM are unique to a single family, which makes genetic data interpretation more difficult. Therefore, clinical features and familial history integration are needed to improve clinical decision making.

Keywords

Acknowledgement

Supported by : Korea National Institute of Health Intramural Research

References

  1. Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol 2013;10:531-47. https://doi.org/10.1038/nrcardio.2013.105
  2. Choi DJ, Han S, Jeon ES, et al. Characteristics, outcomes and predictors of long-term mortality for patients hospitalized for acute heart failure: a report from the korean heart failure registry. Korean Circ J 2011;41:363-71. https://doi.org/10.4070/kcj.2011.41.7.363
  3. Mahon NG, Murphy RT, MacRae CA, Caforio AL, Elliott PM, McKenna WJ. Echocardiographic evaluation in asymptomatic relatives of patients with dilated cardiomyopathy reveals preclinical disease. Ann Intern Med 2005;143:108-15. https://doi.org/10.7326/0003-4819-143-2-200507190-00009
  4. Herman DS, Lam L, Taylor MR, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med 2012;366:619-28. https://doi.org/10.1056/NEJMoa1110186
  5. Garcia-Pavia P, Cobo-Marcos M, Guzzo-Merello G, et al. Genetics in dilated cardiomyopathy. Biomark Med 2013;7:517-33. https://doi.org/10.2217/bmm.13.77
  6. Gregorio CC, Granzier H, Sorimachi H, Labeit S. Muscle assembly: a titanic achievement? Curr Opin Cell Biol 1999;11:18-25. https://doi.org/10.1016/S0955-0674(99)80003-9
  7. Chauveau C, Rowell J, Ferreiro A. A rising titan: TTN review and mutation update. Hum Mutat 2014;35:1046-59. https://doi.org/10.1002/humu.22611
  8. 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;41:771-80. https://doi.org/10.1016/S0735-1097(02)02954-6
  9. Brodt C, Siegfried JD, Hofmeyer M, et al. Temporal relationship of conduction system disease and ventricular dysfunction in LMNA cardiomyopathy. J Card Fail 2013;19:233-9. https://doi.org/10.1016/j.cardfail.2013.03.001
  10. Morimoto S. Sarcomeric proteins and inherited cardiomyopathies. Cardiovasc Res 2008;77:659-66.
  11. Lakdawala NK, Funke BH, Baxter S, et al. Genetic testing for dilated cardiomyopathy in clinical practice. J Card Fail 2012;18:296-303. https://doi.org/10.1016/j.cardfail.2012.01.013
  12. McNally EM, Golbus JR, Puckelwartz MJ. Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest 2013;123:19-26. https://doi.org/10.1172/JCI62862
  13. 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;332:1058-64. https://doi.org/10.1056/NEJM199504203321603
  14. Brauch KM, Karst ML, Herron KJ, et al. Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. J Am Coll Cardiol 2009;54:930-41. https://doi.org/10.1016/j.jacc.2009.05.038
  15. Guo W, Schafer S, Greaser ML, et al. RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat Med 2012;18:766-73. https://doi.org/10.1038/nm.2693
  16. Norton N, Li D, Rieder MJ, et al. Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. Am J Hum Genet 2011;88:273-82. https://doi.org/10.1016/j.ajhg.2011.01.016
  17. Homma S, Iwasaki M, Shelton GD, Engvall E, Reed JC, Takayama S. BAG3 deficiency results in fulminant myopathy and early lethality. Am J Pathol 2006;169:761-73. https://doi.org/10.2353/ajpath.2006.060250
  18. 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;33:723-32. https://doi.org/10.1006/jmcc.2000.1339
  19. Norgett EE, Hatsell SJ, Carvajal-Huerta L, et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet 2000;9:2761-6. https://doi.org/10.1093/hmg/9.18.2761
  20. Yang Z, Bowles NE, Scherer SE, et al. Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Res 2006;99:646-55. https://doi.org/10.1161/01.RES.0000241482.19382.c6
  21. Remme CA, Wilde AA. SCN5A overlap syndromes: no end to disease complexity? Europace 2008;10:1253-5. https://doi.org/10.1093/europace/eun267
  22. Takai E, Akita H, Shiga N, et al. Mutational analysis of the cardiac actin gene in familial and sporadic dilated cardiomyopathy. Am J Med Genet 1999;86:325-7. https://doi.org/10.1002/(SICI)1096-8628(19991008)86:4<325::AID-AJMG5>3.0.CO;2-U
  23. Harris SP, Bartley CR, Hacker TA, et al. Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice. Circ Res 2002;90:594-601. https://doi.org/10.1161/01.RES.0000012222.70819.64
  24. Carballo S, Robinson P, Otway R, et al. Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy. Circ Res 2009;105:375-82. https://doi.org/10.1161/CIRCRESAHA.109.196055
  25. Steward CG, Newbury-Ecob RA, Hastings R, et al. Barth syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth. Prenat Diagn 2010;30:970-6. https://doi.org/10.1002/pd.2599
  26. Roberts AE, Nixon C, Steward CG, et al. The Barth Syndrome Registry: distinguishing disease characteristics and growth data from a longitudinal study. Am J Med Genet A 2012;158A:2726-32. https://doi.org/10.1002/ajmg.a.35609
  27. Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MR, Towbin JA. Genetic evaluation of cardiomyopathy-a Heart Failure Society of America practice guideline. J Card Fail 2009;15:83-97. https://doi.org/10.1016/j.cardfail.2009.01.006
  28. 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;8:1308-39. https://doi.org/10.1016/j.hrthm.2011.05.020

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