Skip to main content Accessibility help
×
Home

A novel MYBPC3 c.2737+1 (IVS26) G>T mutation responsible for high-risk hypertrophic cardiomyopathy

  • Wuyang Tong (a1), Wei Liu (a2), Hong Guo (a3), Jiang Wang (a1), Shiyong Yu (a1), Jihang Zhang (a1), Chuan Liu (a1), Jia Chen (a4) and Xiaohui Zhao (a1)...

Abstract

Background:

Hypertrophic cardiomyopathy is an autosomal dominant hereditary disease characterised by left ventricular asymmetry hypertrophy. However, our knowledge of the genetic background in hypertrophic cardiomyopathy cases is limited. Here, we aimed to evaluate pathogenic gene mutations in a family with high-risk hypertrophic cardiomyopathy and analyse the genotype/phenotype relationships in this family.

Methods:

The proband, her parents, and her niece underwent whole-exome sequencing, and the genotypes of family members were identified using Sanger sequencing. mRNA expression was detected using reverse transcription sequencing. Structural impairments were predicted by homologous modelling. A family survey was conducted for patients with positive results to obtain information on general clinical symptoms, electrocardiography, ambulatory electrocardiography, echocardiography, and 3.0T cardiac magnetic resonance findings. Regular follow-up was performed for up to 6 months.

Results:

Five family members, including the proband, carried a cleavage site mutation in the MYBPC3 gene (c.2737+1 (IVS26) G>T), causing exon 26 of the MYBPC3 gene transcript to be skipped and leading to truncation of cardiac myosin-binding protein C. Family survey showed that the earliest onset age was 13 years old, and three people had died suddenly at less than 40 years old. Three pathogenic gene carriers were diagnosed with hypertrophic cardiomyopathy, and all showed severe ventricular septal hypertrophy.

Conclusion:

The c.2737+1 (IVS26) G>T mutation in the MYBPC3 gene led to exon 26 skipping, thereby affecting the structure and function of cardiac myosin-binding protein C and leading to severe ventricular hypertrophy and sudden death.

Copyright

Corresponding author

Author for correspondence: X. Zhao, MD, Institute of Cardiovascular Research, Xinqiao Hospital, Army Medical University, 183 Xinqiao Road, Shapingba District, Chongqing 400037, China. Tel: +8613508332848. E-mail: doctorzhaoxiaohui@yahoo.com

References

Hide All
1. Spirito, P, Autore, C, Formisano, F, et al. Risk of sudden death and outcome in patients with hypertrophic cardiomyopathy with benign presentation and without risk factors. Am J Cardiol 2014; 113: 15501555.
2. Veselka, J, Zemánek, D, Jahnlová, D, et al. Risk and causes of death in patients after alcohol septal ablation for hypertrophic obstructive cardiomyopathy. Can J Cardiol 2015; 31: 12451251.
3. Maron, BJ, Rowin, EJ, Casey, SA, et al. Hypertrophic cardiomyopathy in adulthood associated with low cardiovascular mortality with contemporary management strategies. J Am Coll Cardiol 2015; 65: 19151928.
4. Pascoe, SJ. Clinical course and management of hypertrophic cardiomyopathy. N Engl J Med 2018; 379: 19761977.
5. Walsh, R, Buchan, R, Wilk, A, et al. Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes. Eur Heart J 2017; 38: 34613468.
6. Walsh, R, Thomson, KL, Ware, JS, et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med 2017; 19: 192203.
7. Akhtar, M, Elliott, P. The genetics of hypertrophic cardiomyopathy. Glob Cardiol Sci Pract 2018; 2018: 36.
8. Marian, AJ, Braunwald, E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res 2017; 121: 749770.
9. Liew, AC, Vassiliou, VS, Cooper, R, Raphael, CE. Hypertrophic cardiomyopathy-past, present and future. J Clin Med 2017; 6: 118.
10. Bamshad, MJ, Ng, SB, Bigham, AW, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 2011; 12: 745755.
11. Leproust, E. Target enrichment strategies for next generation sequencing. Mlo Med Lab Obs 2012; 44: 2627.
12. Petersen, BS, Fredrich, B, Hoeppner, MP, Ellinghaus, D, Franke, A. Opportunities and challenges of whole-genome and -exome sequencing. BMC Genet 2017; 18: 14.
13. Rayment, I, Holden, HM, Sellers, JR, Fananapazir, L, Epstein, ND. Structural interpretation of the mutations in the beta-cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy. Proc Natl Acad Sci U S A 1995; 92: 38643868.
14. Woo, A, Rakowski, H, Liew, JC, et al. Mutations of the beta myosin heavy chain gene in hypertrophic cardiomyopathy: critical functional sites determine prognosis. Heart 2003; 89: 11791185.
15. Elliott, PM, Anastasakis, A, Borger, MA, et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the task force for the diagnosis and management of hypertrophic cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014; 35: 27332779.
16. Richards, S, Aziz, N, Bale, S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med 2015; 17: 405424.
17. Carrier, L, Mearini, G, Stathopoulou, K, Cuello, F. Cardiac myosin-binding protein C (MYBPC3) in cardiac pathophysiology. Gene 2015; 573: 188197.
18. Sakamoto, N, Kawamura, Y, Sato, N, et al. Late gadolinium enhancement on cardiac magnetic resonance represents the depolarizing and repolarizing electrically damaged foci causing malignant ventricular arrhythmia in hypertrophic cardiomyopathy. Heart Rhythm 2015; 12: 12761284.
19. Charron, P, Dubourg, O, Desnos, M, et al. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene. Circulation 1998; 97: 22302236.
20. Niimura, H, Bachinski, LL, Sangwatanaroj, S, et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 1998; 338: 12481257.
21. Erdmann, J, Raible, J, Maki-Abadi, J, et al. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. J Am Coll Cardiol 2001; 38: 322330.
22. Gilbert, R, Kelly, MG, Mikawa, T, Fischman, DA. The carboxyl terminus of myosin binding protein C (MyBP-C, C-protein) specifies incorporation into the A-band of striated muscle. J Cell Sci 1996; 109 (Pt 1): 101111.
23. Gilbert, R, Cohen, JA, Pardo, S, Basu, A, Fischman, DA. Identification of the A-band localization domain of myosin binding proteins C and H (MyBP-C, MyBP-H) in skeletal muscle. J Cell Sci 1999; 112 (Pt 1): 6979.
24. Freiburg, A, Gautel, M. A molecular map of the interactions between titin and myosin-binding protein C. Implications for sarcomeric assembly in familial hypertrophic cardiomyopathy. Eur J Biochem 1996; 235: 317323.
25. Monteiro, DRA, Guerrero-Serna, G, Helms, A, et al. Deficient cMyBP-C protein expression during cardiomyocyte differentiation underlies human hypertrophic cardiomyopathy cellular phenotypes in disease specific human ES cell derived cardiomyocytes. J Mol Cell Cardiol 2016; 99: 197206.
26. Prondzynski, M, Mearini, G, Carrier, L. Gene therapy strategies in the treatment of hypertrophic cardiomyopathy. Pflugers Arch 2019; 471: 807815.
27. Hammond, SM, Wood, MJ. Genetic therapies for RNA mis-splicing diseases. Trends Genet 2011; 27: 196205.
28. Gedicke-Hornung, C, Behrens-Gawlik, V, Reischmann, S, et al. Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice. Embo Mol Med 2013; 5: 11281145.
29. Garcia-Giustiniani, D, Arad, M, Ortiz-Genga, M, et al. Phenotype and prognostic correlations of the converter region mutations affecting the beta myosin heavy chain. Heart 2015; 101: 10471053.

Keywords

Type Description Title
WORD
Supplementary materials

Tong et al. supplementary material
Tong et al. supplementary material 1

 Word (18 KB)
18 KB
WORD
Supplementary materials

Tong et al. supplementary material
Tong et al. supplementary material 2

 Word (15 KB)
15 KB
UNKNOWN
Supplementary materials

Tong et al. supplementary material
Tong et al. supplementary material 3

 Unknown (5.0 MB)
5.0 MB

A novel MYBPC3 c.2737+1 (IVS26) G>T mutation responsible for high-risk hypertrophic cardiomyopathy

  • Wuyang Tong (a1), Wei Liu (a2), Hong Guo (a3), Jiang Wang (a1), Shiyong Yu (a1), Jihang Zhang (a1), Chuan Liu (a1), Jia Chen (a4) and Xiaohui Zhao (a1)...

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed