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Whole-exome sequencing reveals doubly novel heterozygous Myosin Binding Protein C and Titin mutations in a Chinese patient with severe dilated cardiomyopathy

Published online by Cambridge University Press:  15 August 2018

Liang-Liang Fan ,
Ya-Qin Chen ,
Hao Huang ,
Jie-Yuan Jin ,
Jing-Jing Li  and
Zhi-Ping Tan
Liang-Liang Fan
Affiliation:
Department of cell biology, the School of Life Sciences, Central South University, Changsha, China
Ya-Qin Chen
Affiliation:
Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, China
Hao Huang
Affiliation:
Department of cell biology, the School of Life Sciences, Central South University, Changsha, China
Jie-Yuan Jin
Affiliation:
Department of cell biology, the School of Life Sciences, Central South University, Changsha, China
Jing-Jing Li
Affiliation:
Department of cell biology, the School of Life Sciences, Central South University, Changsha, China
Zhi-Ping Tan*
Affiliation:
Department of Cardiothoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China
*
Author for correspondence: Zhi-Ping Tan, PhD, Department of Cardiothoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha 410011, People’s Republic of China; E-mail: zhipingtan@csu.edu.cn
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Abstract

Background

Dilated Cardiomyopathy is a serious heart disorder that may induce sudden cardiac death and heart failure. Significant progress has been made in understanding the molecular basis of dilated cardiomyopathy. In previous studies, mutations in more than fifty genes have been identified in dilated cardiomyopathy patients. The purpose of this study was to detect the genetic lesion in a family from the central south of China affected by severe dilated cardiomyopathy.

Methods

Whole-exome sequencing combined with cardiomyopathy-related genes list were used to analyse the mutations of the proband. Co-segregation analysis was performed by Sanger sequencing.

Results and conclusions

Two novel heterozygous mutations – Myosin Binding Protein C: p.L1014RfsX6 and Titin: p.R9793X – were identified in the proband. The deletion mutation c.3041delT/p.L1014RfsX6 caused a premature stop codon at position 1020 in exon 28 of the Myosin Binding Protein C. The nonsense mutation, c.29377 C>T/ p. R9793X, of Titin was located in the highly evolutionarily conserved domain, resulting in truncation of the Titin protein as well. Co-segregation analysis further revealed that the Myosin Binding Protein C mutation came from his mother and the Titin mutation came from his father. Both mutations are reported in dilated cardiomyopathy patients for the first time. Our study not only provides a unique example of the genes and molecular mechanisms involved in dilated cardiomyopathy but also expands the spectrum of Myosin Binding Protein C and Titin mutations and contributes to the genetic diagnosis and counselling of dilated cardiomyopathy patients.

Keywords

Dilated cardiomyopathyMyosin Binding Protein CTitindoubly heterozygous mutations

Information

Type
Original Article
Information
Cardiology in the Young , Volume 28 , Issue 12 , December 2018 , pp. 1410 - 1414
Copyright
© Cambridge University Press 2018 

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References

1. Hershberger, RE, Hedges, DJ, Morales, A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol 2013; 10: 531–547.Google Scholar
2. McNally, EM, Mestroni, L. Dilated cardiomyopathy: genetic determinants and mechanisms. Circulation research 2017; 121: 731–748.Google Scholar
3. Fan, LL, Huang, H, Jin, JY, et al. Whole exome sequencing identifies a novel mutation (c.333+2T>C) of TNNI3K in a Chinese family with dilated cardiomyopathy and cardiac conduction disease. Gene 2018; 648: 63–67.C)+of+TNNI3K+in+a+Chinese+family+with+dilated+cardiomyopathy+and+cardiac+conduction+disease.+Gene+2018;+648:+63–67.>Google Scholar
4. Liu, JS, Fan, LL, Zhang, H, et al. Whole-exome sequencing identifies two novel TTN mutations in Chinese families with dilated cardiomyopathy. Cardiology 2017; 136: 10–14.Google Scholar
5. Weintraub, RG, Semsarian, C, Macdonald, P. Dilated cardiomyopathy. Lancet 2017; 390: 400–414.Google Scholar
6. Bezzina, CR, Lahrouchi, N, Priori, SG. Genetics of sudden cardiac death. Circ Res 2015; 116: 1919–1936.Google Scholar
7. Perez-Serra, A, Toro, R, Sarquella-Brugada, G, et al. Genetic basis of dilated cardiomyopathy. Int J Cardiol 2016; 224: 461–472.Google Scholar
8. Haas, J, Frese, KS, Peil, B, et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J 2015; 36: 1123–1135a.Google Scholar
9. Roncarati, R, Viviani Anselmi, C, Krawitz, P, et al. Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy. Eur J Hum Genet 2013; 21: 1105–1111.Google Scholar
10. Millat, G, Bouvagnet, P, Chevalier, P, et al. Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy. Eur J Med Genet 2011; 54: e570–575.Google Scholar
11. Xiang, R, Fan, LL, Huang, H, et al. A novel mutation of GATA4 (K319E) is responsible for familial atrial septal defect and pulmonary valve stenosis. Gene 2014; 534: 320–323.Google Scholar
12. McNally, EM, Golbus, JR, Puckelwartz, MJ. Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest 2013; 123: 19–26.Google Scholar
13. van Velzen, HG, Schinkel, AFL, Oldenburg, RA, et al. Clinical characteristics and long-term outcome of hypertrophic cardiomyopathy in individuals with a myosin binding protein C (myosin-binding protein C) founder mutation. Circ Cardiovasc Genet 2017: 10.Google Scholar
14. Liu, X, Jiang, T, Piao, C, et al. Screening mutations of myosin binding protein C in 114 unrelated patients with hypertrophic cardiomyopathy by targeted capture and next-generation sequencing. Sci Rep 2015; 5: 11411.Google Scholar
15. Gresham, KS, Stelzer, JE. The contributions of cardiac myosin binding protein C and troponin I phosphorylation to beta-adrenergic enhancement of in vivo cardiac function. J Physiol 2016; 594: 669–686.Google Scholar
16. Kumar, M, Govindan, S, Zhang, M, et al. Cardiac myosin-binding protein C and troponin-I phosphorylation independently modulate myofilament length-dependent activation. J Biol Chem 2015; 290: 29241–29249.Google Scholar
17. Ito, K, Patel, PN, Gorham, JM, et al. Identification of pathogenic gene mutations in LMNA and Myosin Binding Protein C that alter RNA splicing. Proc Natl Acad Sci U S A 2017; 114: 7689–7694.Google Scholar
18. Kuster, DW, Govindan, S, Springer, TI, Martin, JL, Finley, NL, Sadayappan, S. A hypertrophic cardiomyopathy-associated myosin binding protein C mutation common in populations of South Asian descent causes contractile dysfunction. J Biol Chem 2015; 290: 5855–5867.Google Scholar
19. Chauveau, C, Rowell, J, Ferreiro, A. A rising titan: TTN review and mutation update. Hum Mutat 2014; 35: 1046–1059.Google Scholar
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