Volume 21, Issue 3 (Pajouhan Scientific Journal, Summer 2023)
Pajouhan Sci J 2023, 21(3): 204-212 |
Back to browse issues page
Ethics code: شناسه: IR.MODARES.REC.1398.218
Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Kaki A, Dalili M, Mahdieh N, Noruzinia M. Genetic Study of Hypertrophic Cardiomyopathy in Iranian Patients: Role of a De Novo Variant. Pajouhan Sci J 2023; 21 (3) :204-212
URL: http://psj.umsha.ac.ir/article-1-1025-en.html
URL: http://psj.umsha.ac.ir/article-1-1025-en.html
1- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran , noruzinia@modares.ac.ir
2- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
3- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
4- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
2- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
3- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
4- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
Abstract: (1920 Views)
Background and Objectives: Hypertrophic cardiomyopathy is a common cardiac disease diagnosed in young adults and rarely detectable in childhood. Hypertrophic cardiomyopathy exhibits considerable diversity in its clinical and genetic characteristics. To date, mutations in multiple genes associated with HCM have been discovered, with the most common ones being MYBPC3 and MYH7 genes. The present study aimed to utilize whole exome sequencing for conducting a genetic analysis of Hypertrophic cardiomyopathy in four children belonging to Iranian families.
Materials and Methods: Patients underwent medical evaluation, including clinical assessment, electrocardiography, and echocardiography. Genetic testing was performed after DNA extraction using whole exome sequencing to identify genetic alterations that may be responsible for this disease. In addition, bioinformatic analysis of the genetic changes was carried out using software tools for alignment, variant calling, and interpretation. Finally, the Sanger sequencing method was employed to confirm the genetic variations in the affected individual's family members.
Results: The patients were children presenting with initial symptoms, such as syncope and palpitations. They were diagnosed with Hypertrophic cardiomyopathy type 3 and 4 based on the results of electrocardiography and echocardiography. The genetic testing results revealed a pathogenic de novo mutation (c.1208G>A, p.Arg403Gln) in the MYH7 gene. In addition, another disease-causing homozygous nonsense genetic variation (c.3811C>T, p.Arg1271Ter) was identified in the MYBPC3 gene, resulting in the production of a premature protein.
Conclusion: This study not only expanded the spectrum of genetic variations associated with Hypertrophic cardiomyopathy disease and aided in genetic counseling for families affected by it but also presented the first variations of the sarcomere gene in Iranian children.
Materials and Methods: Patients underwent medical evaluation, including clinical assessment, electrocardiography, and echocardiography. Genetic testing was performed after DNA extraction using whole exome sequencing to identify genetic alterations that may be responsible for this disease. In addition, bioinformatic analysis of the genetic changes was carried out using software tools for alignment, variant calling, and interpretation. Finally, the Sanger sequencing method was employed to confirm the genetic variations in the affected individual's family members.
Results: The patients were children presenting with initial symptoms, such as syncope and palpitations. They were diagnosed with Hypertrophic cardiomyopathy type 3 and 4 based on the results of electrocardiography and echocardiography. The genetic testing results revealed a pathogenic de novo mutation (c.1208G>A, p.Arg403Gln) in the MYH7 gene. In addition, another disease-causing homozygous nonsense genetic variation (c.3811C>T, p.Arg1271Ter) was identified in the MYBPC3 gene, resulting in the production of a premature protein.
Conclusion: This study not only expanded the spectrum of genetic variations associated with Hypertrophic cardiomyopathy disease and aided in genetic counseling for families affected by it but also presented the first variations of the sarcomere gene in Iranian children.
Type of Study: Research Article |
Subject:
Medicine & Clinical Sciences
Received: 2023/06/3 | Accepted: 2023/06/13 | Published: 2023/09/22
Received: 2023/06/3 | Accepted: 2023/06/13 | Published: 2023/09/22
References
1. Maron BJ, Desai MY, Nishimura RA, Spirito P, Rakowski H, Towbin JA, et al. Diagnosis and Evaluation of Hypertrophic Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2022;79(4):372-89. [DOI:10.1016/j.jacc.2021.12.002] [PMID]
2. Melas M, Beltsios ET, Adamou A, Koumarelas K, McBride KL. Molecular diagnosis of hypertrophic cardiomyopathy (HCM): In the heart of cardiac disease. J Clin Med. 2022;12(1):225. [DOI:10.3390/jcm12010225] [PMID] []
3. Carrier L, Mearini G, Stathopoulou K, Cuello F. Cardiac myosin-binding protein C (MYBPC3) in cardiac pathophysiology. Gene.
4. Helms AS, Thompson AD, Glazier AA, Hafeez N, Kabani S, Rodriguez J, et al. Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy. Circ Genomic Precis Med. 2020;13(5):396-405. [DOI:10.1161/CIRCGEN.120.002929] [PMID] []
5. Toepfer CN, Wakimoto H, Garfinkel AC, McDonough B, Liao D, Jiang J, et al. Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin. Sci Transl Med. 2019;11(476):eaat1199. [DOI:10.1126/scitranslmed.aat1199] [PMID] []
6. Qin H, Kemp J, Yip MY, Lam-Po-Tang PRL, Hoh JFY, Morris BJ. Localization of human cardiac β-myosin heavy chain gene (MYH7) to chromosome 14q12 by in situ hybridization. Cytogenet Cell Genet. 1990;54(1-2):74-6. [DOI:10.1159/000132961] [PMID]
7. Liu HT, Ji FF, Wei L, Zuo AJ, Gao YX, Qi L, et al. Screening of MYH7 gene mutation sites in hypertrophic cardiomyopathy and its significance. Chin Med J (Engl). 2019;132(23):2835-41. [DOI:10.1097/CM9.0000000000000428] [PMID] []
8. Ommen SR, Mital S, Burke MA, Day SM, Deswal A, Elliott P, et al. 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy. J Thorac Cardiovasc Surg. 2021;162(1).
9. Andrews S. Babraham Bioinformatics - FastQC A quality control tool for high throughput sequence data. Illumina. 2020;5.
10. Bolger AM, Lohse M, Usadel B. Trimmomatic: A flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30(15):2114-20. [DOI:10.1093/bioinformatics/btu170] [PMID] []
11. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754-60. [DOI:10.1093/bioinformatics/btp324] [PMID] []
12. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The genome analysis toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20(9):1297-303. [DOI:10.1101/gr.107524.110] [PMID] []
13. McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GRS, Thormann A, et al. The ensembl variant effect predictor. Genome Biol. 2016;17(1):122. [DOI:10.1186/s13059-016-0974-4] [PMID] []
14. Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: Predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47(D1):886-94. [DOI:10.1093/nar/gky1016] [PMID] []
15. 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. Genet Med. 2015;17(5):405-24. [DOI:10.1038/gim.2015.30] [PMID] []
16. Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. SIFT web server: Predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012;40(W1):452-7. [DOI:10.1093/nar/gks539] [PMID] []
17. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013;7. [DOI:10.1002/0471142905.hg0720s76] [PMID] []
18. Steinhaus R, Proft S, Schuelke M, Cooper DN, Schwarz JM, Seelow D. MutationTaster2021. Nucleic Acids Res. 2021;49(1):446-51. [DOI:10.1093/nar/gkab266] [PMID] []
19. Marian AJ, Braunwald E. Hypertrophic cardiomyopathy: Genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res. 2017;121(7):749-70. [DOI:10.1161/CIRCRESAHA.117.311059] [PMID] []
20. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: Clinical perspectives. J Am Coll Cardiol. 2012;60(8):705-15. [DOI:10.1016/j.jacc.2012.02.068] [PMID]
21. Franaszczyk M, Truszkowska G, Chmielewski P, Rydzanicz M, Kosinska J, Rywik T, et al. Analysis of de novo mutations in sporadic cardiomyopathies emphasizes their clinical relevance and points to novel candidate genes. J Clin Med. 2020;9(2):370. [DOI:10.3390/jcm9020370] [PMID] []
22. Wessels MW, Herkert JC, Frohn-Mulder IM, Dalinghaus M, Van Den Wijngaard A, De Krijger RR, et al. Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects. Eur J Hum Genet. 2015;23(7):922-8. [DOI:10.1038/ejhg.2014.211] [PMID] []
23. Mak T, Lee YK, Tang CS, Hai J, Ran X, Sham PC, et al. Coverage and diagnostic yield of Whole Exome Sequencing for the Evaluation of Cases with Dilated and Hypertrophic Cardiomyopathy. Sci Rep. 2018;8(1). [DOI:10.1038/s41598-018-29263-3] [PMID] []
Send email to the article author
| Rights and permissions | |
 |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
Articles Copyright © The Author(s).
Owned by Hamadan University of Medical Sciences.
Published by UMSHA Press
Journal Tel: +98 81 38380090
Publisher Tel: +98 81 38382022
Website: https://psj.umsha.ac.ir/
Email: psj@umsha.ac.ir
