No Effect of the p.Arg230His Variant Of The VCL Protein on the Course of the Hypertrophic Cardiomyopathy In Russian Family Carrying The p.Gln1233Ter Pathogenic Variant In The MYBPC3 Gene

Aim      To determine specific clinical characteristics caused by a combination of the rs397516037 pathogenic variant in the myosin-binding protein C (MTBPC3) and the rs749628307 polymorphic variant in the vinculin (VCL) gene in a Russian family of carriers and to evaluate the contribution of the rs749628307 polymorphic variant in the VCL gene to the development of hypertrophic cardiomyopathy (HCMP).

Material and methods  The family under study included one healthy person and 3 patients with HCMP. A targeted analysis of proband’s exome was performed. A structural alignment for both forms of the VCL protein, the canonical form and the form with p.Arg230His substitution, was performed.

Results The pathogenic rs397516037 variant and the potentially pathogenic rs749628307 variant were detected in the proband and several family members. A possibly damaging variant rs749628307 was detected in the proband and several family members evaluated in this study. The structural alignment confirmed that the rs749628307 variant did not alter the protein structure significantly and could not cause an impairment or loss of the protein function.

Conclusion      This study demonstrated that apparently the rs749628307 variant in the VCL gene does not affect the protein structure in a pathogenetically significant way, neither does it affect the severity and form of the clinical manifestations of HCMP; therefore, it cannot be considered as pathogenic.

1. Semsarian C, Ingles J, Maron MS, Maron BJ. New Perspectives on the Prevalence of Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology. 2015;65(12):1249–54. DOI: 10.1016/j.jacc.2015.01.019

2. Maron BJ. Hypertrophic Cardiomyopathy: A Systematic Review. JAMA. 2002;287(10):1308–20. DOI: 10.1001/jama.287.10.1308

3. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet. 2013;381(9862):242–55. DOI: 10.1016/S0140-6736(12)60397-3

4. Greaves SC, Roche AH, Neutze JM, Whitlock RM, Veale AM. Inheritance of hypertrophic cardiomyopathy: a cross sectional and M mode echocardiographic study of 50 families. Heart. 1987;58(3):259–66. DOI: 10.1136/hrt.58.3.259

5. Ho CY, Charron P, Richard P, Girolami F, Van Spaendonck-Zwarts KY, Pinto Y. Genetic advances in sarcomeric cardiomyopathies: state of the art. Cardiovascular Research. 2015;105(4):397–408. DOI: 10.1093/cvr/cvv025

6. Maron BJ, Maron MS, Semsarian C. Genetics of Hypertrophic Cardiomyopathy After 20 Years: clinical perspectives. Journal of the American College of Cardiology. 2012;60(8):705–15. DOI: 10.1016/j.jacc.2012.02.068

7. Watkins H, Anan R, Coviello DA, Spirito P, Seidman JG, Seidman CE. A De Novo Mutation in α-Tropomyosin That Causes Hypertrophic Cardiomyopathy. Circulation. 1995;91(9):2302–5. DOI: 10.1161/01.CIR.91.9.2302

8. Branzi A, Romeo G, Specchia S, Lolli C, Binetti G, Devoto M et al. Genetic heterogeneity of hypertrophic cardiomyopathy. International Journal of Cardiology. 1985;7(2):129–33. DOI: 10.1016/0167-5273(85)90352-3

9. Hagen CM, Aidt FH, Havndrup O, Hedley PL, Jensen MK, Kanters JK et al. Private Mitochondrial DNA Variants in Danish Patients with Hypertrophic Cardiomyopathy. PLOS ONE. 2015;10(4):e0124540. DOI: 10.1371/journal.pone.0124540

10. Hartmannova H, Kubanek M, Sramko M, Piherova L, Noskova L, Hodanova K et al. Isolated X-Linked Hypertrophic Cardiomyopathy Caused by a Novel Mutation of the Four-and-a-Half LIM Domain 1 Gene. Circulation: Cardiovascular Genetics. 2013;6(6):543–51. DOI: 10.1161/CIRCGENETICS.113.000245

11. Santorelli FM, Tanji K, Manta P, Casali C, Krishna S, Hays AP et al. Maternally Inherited Cardiomyopathy: An Atypical Presentation of the mtDNA 12S rRNA Gene A1555G Mutation. The American Journal of Human Genetics. 1999;64(1):295–300. DOI: 10.1086/302188

12. Das K J, Ingles J, Bagnall RD, Semsarian C. Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment. Genetics in Medicine. 2014;16(4):286–93. DOI: 10.1038/gim.2013.138

13. Erdmann J, Raible J, Maki-Abadi J, Hammann J, Wollnik B, Frantz E et al. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. Journal of the American College of Cardiology. 2001;38(2):322–30. DOI: 10.1016/S0735-1097(01)01387-0

14. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C et al. Hypertrophic Cardiomyopathy: Distribution of Disease Genes, Spectrum of Mutations, and Implications for a Molecular Diagnosis Strategy. Circulation. 2003;107(17):2227–32. DOI: 10.1161/01.CIR.0000066323.15244.54

15. Van Driest SL, Vasile VC, Ommen SR, Will ML, Tajik AJ, Gersh BJ et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. Journal of the American College of Cardiology. 2004;44(9):1903–10. DOI: 10.1016/j.jacc.2004.07.045

16. Cecconi M, Parodi MI, Formisano F, Spirito P, Autore C, Musumeci MB et al. Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy. International Journal of Molecular Medicine. 2016;38(4):1111–24. DOI: 10.3892/ijmm.2016.2732

17. Ehlermann P, Weichenhan D, Zehelein J, Steen H, Pribe R, Zeller R et al. Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3gene. BMC Medical Genetics. 2008;9(1):95. DOI: 10.1186/1471-2350-9-95

18. Fokstuen S, Lyle R, Munoz A, Gehrig C, Lerch R, Perrot A et al. A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy. Human Mutation. 2008;29(6):879–85. DOI: 10.1002/humu.20749

19. Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. Journal of Medical Genetics. 2005;42(10):e59–e59. DOI: 10.1136/jmg.2005.033886

20. Kapplinger JD, Landstrom AP, Bos JM, Salisbury BA, Callis TE, Ackerman MJ. Distinguishing Hypertrophic Cardiomyopathy-Associated Mutations from Background Genetic Noise. Journal of Cardiovascular Translational Research. 2014;7(3):347–61. DOI: 10.1007/s12265-014-9542-z

21. Tóth T, Nagy V, Faludi R, Csanády M, Nemes A, Simor T et al. The Gln1233ter mutation of the myosin binding protein C gene: Causative mutation or innocent polymorphism in patients with hypertrophic cardiomyopathy? International Journal of Cardiology. 2011;153(2):216–9. DOI: 10.1016/j.ijcard.2011.09.062

22. Zeller R, Ivandic BT, Ehlermann P, Mücke O, Zugck C, Remppis A et al. Large-scale mutation screening in patients with dilated or hypertrophic cardiomyopathy: a pilot study using DGGE. Journal of Molecular Medicine. 2006;84(8):682–91. DOI: 10.1007/s00109-006-0056-2

23. Filatova EV, Krylova NS, Vlasov IN, Maslova MS, Poteshkina NG, Slominsky PA et al. Targeted exome analysis of Russian patients with hypertrophic cardiomyopathy. Molecular Genetics & Genomic Medicine. 2021;9(11):e1808. DOI: 10.1002/mgg3.1808

24. Zhang Y. I-TASSER: Fully automated protein structure prediction in CASP8. Proteins: Structure, Function, and Bioinformatics. 2009;77(S9(Suppl 9)):100–13. DOI: 10.1002/prot.22588

25. Yang J, Zhang Y. I-TASSER server: new development for protein structure and function predictions. Nucleic Acids Research. 2015;43(W1):W174–81. DOI: 10.1093/nar/gkv342

26. Roy A, Yang J, Zhang Y. COFACTOR: an accurate comparative algorithm for structure-based protein function annotation. Nucleic Acids Research. 2012;40(W1):W471–7. DOI: 10.1093/nar/gks372

27. Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum MJ et al. ClinGen – The Clinical Genome Resource. New England Journal of Medicine. 2015;372(23):2235–42. DOI: 10.1056/NEJMsr1406261

28. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J 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. Genetics in Medicine. 2015;17(5):405–24. DOI: 10.1038/gim.2015.30