Whole exome sequencing identifies variants in the \(\textit{TNNI3}\) gene in vietnamese patient with restrictive cardiomyopathy - a case report

Nguyen Thi Kim Lien, Nguyen Van Tung, Le Trong Tu, Dang Thi Hai Van, Vu Quynh Nga, Nguyen Thanh Hien, Do Minh Hien, Nguyen Hoang Lam, Trinh Tuan Hien, Nguyen Minh Duc, Nguyen Huy Hoang
Author affiliations


  • Nguyen Thi Kim Lien Institute of Genome Research
  • Nguyen Van Tung
  • Le Trong Tu
  • Dang Thi Hai Van
  • Vu Quynh Nga
  • Nguyen Thanh Hien
  • Do Minh Hien
  • Nguyen Hoang Lam
  • Trinh Tuan Hien
  • Nguyen Minh Duc
  • Nguyen Huy Hoang




Mutation, Restrictive cardiomyopathy (RCM), TNNI3 gene, Vietnamese patient, Whole exome sequencing (WES).


Restrictive cardiomyopathy (RCM) is a rare heart muscle disease in which the heart wall is rigid leading to diastolic dysfunction caused by abnormal elastic properties of the myocardium and/or intercellular matrix. The prognosis is generally poor, and RCM has a high mortality rate in pediatric patients. There are no curative treatments for RCM, so cardiac transplantation is the only effective treatment. Diagnosis RCM, clinical diagnosis can be challenging because clinical presentations and imaging manifestations of RCM are similar to other cardiomyopathies so it requires other specific diagnoses. Currently, pathogenic mutations in 22 different genes have been identified in patients with RCM. Identifying mutations in these genes helps discriminate RCM from other cardiomyopathies. Besides, next-generation sequencing (including whole genome sequencing, whole exome sequencing,...) has provided an effective tool for simultaneously analyzing mutations in many different genes.

In this study, we conducted sequencing of the entire gene coding region (WES) in the patient and identified a compound heterozygote variants (c.289C>G, p.Arg97Gly and c.433C>T, p.Arg145Trp) in the TNNI3 gene. These variants were inherited from the patient's father and mother, who were heterozygous variant carriers. These variants were also identified as the pathogenic variants in the ClinVar database (accession number VCV001331910.2 and VCV000012426.28, respectively) and were the cause of the patient's disease. Our results suggest that WES can be used to definitively diagnose the genetic variants associated with RCM and show that genetic screening is essential for families of RCM patients.


Download data is not yet available.


Metrics Loading ...


Bhavsar P. K., Brand N. J., Yacoub M. H., & Barton P. J., 1996. Isolation and characterization of the human cardiac troponin I gene (TNNI3). Genomics, 35: 11–23.

Bicer M., Ozdemir B., Kan I., Yuksel A., Tok M., & Senkaya I., 2015. Long-term outcomes of pericardiectomy for constrictive pericarditis. Journal of Cardiothoracic Surgery, 10: 177.

Brodehl A., Pour Hakimi S. A., Stanasiuk C., Ratnavadivel S., Hendig D., Gaertner A., Gerull B., Gummert J., Paluszkiewicz L., & Milting H., 2019. Restrictive cardiomyopathy is caused by a novel homozygous Desmin (DES) mutation p.Y122H leading to a severe filament assembly defect. Genes (Basel), 10: 11.

Brodehl A., & Gerull B., 2022. Genetic insights into primary restrictive cardiomyopathy. Preprints, 2022: 0265.

Chen S., Balfour I. C., & Jureidini S., 2001. Clinical spectrum of restrictive cardiomyopathy in children. The Journal of Heart and Lung Transplantation, 20: 90–92.

Cimiotti D., Budde H., Hassoun R.. & Jaquet K., 2021. Genetic restrictive cardiomyopathy: Causes and consequences - An integrative approach. International Journal of Molecular Sciences, 22: 558.

De Pasquale E. C., Nasir K., & Jacoby D. L., 2012. Outcomes of adults with restrictive cardiomyopathy after heart transplantation. The Journal of Heart and Lung Transplantation, 31(12): 1269–1275.

Ding W. H., Han L., Xiao Y. Y., Mo Y., Yang J., Wang X. F., & Jin M., 2017. Role of whole-exome sequencing in phenotype classification and clinical treatment of pediatric restrictive cardiomyopathy. Chinese Medical Journal, 130: 2823–2828.

Elliott P., Andersson B., Arbustini E., Bilinska Z., Cecchi F., Charron P., Dubourg O., Kuhl U., Maisch B., McKenna W. J., Monserrat L., Pankuwweit S., Rapezzi C., Seferovic P., Tawazzi L., & Keren A., 2007. Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. European Heart Journal, 29: 270–276.

Gerhardt T., Monserrat L., Landmesser U., & Poller W., 2022. A novel Troponin I mutation associated with severe restrictive cardiomyopathy - a case report of a 27-year-old woman with fatigue. European Heart Journal - Case Reports, 6(2): 1–6.

Gomes A. V., Liang J., & Potter J. D., 2005. Mutations in human cardiac troponin I that are associated with restrictive cardiomyopathy affect basal ATPase activity and the calcium sensitivity of force development. Journal of Biological Chemistry, 280: 30909–30915.

Hayashi T., Tanimoto K., Hirayama-Yamada K., Tsuda E., Ayusawa M., Nunoda S., Hosaki A., & Kimura A., 2018. Genetic background of Japanese patients with pediatric hypertrophic and restrictive cardiomyopathy. Journal of Human Genetics, 63(9): 989–996.

Huang X. P., & Du J. F., 2004. Troponin I, cardiac diastolic dysfunction and restrictive cardiomyopathy. Acta Pharmacologica Sinica, 25(12): 1569–1575. PMID: 15569399

Hwang J. W., Jang M. A., Jang S. Y., Seo S. H., Seong M. W., Park S. S., Ki C. S., & Kim D. K., 2017. Diverse phenotypic expression of cardiomyopathies in a family with TNNI3 p.Arg145Trp mutation. Korean Circulation Journal, 47(2): 270–277.

Kaski J. P., Syrris P., Burch M., Tome M. T., Fenton M., Christiansen M., Andersen P. S., Sebire N., Ashworth M., Deanfield J. E., McKenna W. J., & Elliott P. M., 2008. Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes. Heart, 94: 1478–1484.

Kostareva A., Kiselev A., Gudkova A., Frishman G., Ruepp A., Frishman D., Ruepp A., Frishman D., Smolina N., Tamovskaya S., Nilsson D., Zlotina A., Khodyuchenko T., Vershinina T., Pervunina T., Klyushina A., Kozlenok A., Sioberg G., Golovliova I., Seiersen T., & Shlyakhlo E., 2016. Genetic spectrum of idiopathic restrictive cardiomyopathy uncovered by next-generation sequencing. PLoS One, 11: e0163362.

Kubo T., Gimeno J. R., Bahl A., Steffensen U., Steffensen M., Osman E., Thaman R., Mogensen J., Elliott P. M., Doi Y., McKenna W. J., 2007. Prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy with restrictive phenotype. Journal of the American College of Cardiology, 49(25): 2419–2426.

Kucera F., & Fenton M., 2017. Update on restrictive cardiomyopathy. Paediatr Child Health, 27(12): 567–571.

Lang R., Gomes A. V., Zhao J., Housmans P. R., Miller T., & Potter J. D., 2002. Functional analysis of a troponin I (R145G) mutation associated with familial hypertrophic cardiomyopathy. Journal of Biological Chemistry, 277: 11670–11678.

Li H., & Durbin R., 2009. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics, 25(14): 1754–1760.

Menon S. C., Michels V. V., Pellikka P. A., Ballew J. D., Karst M. L., Herron K. J., Nelson S. M., Rodeheffer R. J., & Olson T. M., 2008. Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology. Clinical Genetics, 74: 445–454.

Mogensen J., Kubo T., Duque M., Uribe W., Shaw A., Murphy R., Gimeno J. R., Elliott P., & McKenna W. J., 2003. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. Journal of Clinical Investigation, 111: 209–216.

Mogensen J., & Arbustini E., 2009. Restrictive cardiomyopathy. Current Opinion in Cardiology, 24: 214–220.

Mogensen J., Hey T., & Lambrecht S., 2015. A systematic review of phenotypic features associated with cardiac troponin I mutations in hereditary cardiomyopathies. Canadian Journal of Cardiology, 31: 1377–1385.

Mouton J. M., Pellizzon A. S., Goosen A., Kinnear C. J., Herbst P. G., Brink P. A., & Moolman-Smook J. C., 2015. Diagnostic disparity and identification of two TNNI3 gene mutations, one novel and one arising de novo, in South African patients with restrictive cardiomyopathy and focal ventricular hypertrophy. Cardiovascular Journal of Africa, 26(2): 63–69.

Muchtar E., Blauwet L. A., & Gertz M. A., 2017. Restrictive cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circulation Research, 121: 819–837.

Murphy A. M., Kogler H., Georgakopoulos D., McDonough J. L., Kass D. A., Van Eyk J. E., & Marban E., 2000. Transgenic mouse model of stunned myocardium. Science, 287: 488–491.

Pantou M. P., Gourzi P., Gkouziouta A., Armenis I., Kaklamanis L., Zygouri C., Constantoulakis P., Adamopoulos S., & Degiannis D., 2019. A case report of recessive restrictive cardiomyopathy caused by a novel mutation in cardiac troponin I (TNNI3). BMC Medical Genetics, 20: 61.

Parvatiyar M. S., Pinto J. R., Dweck D., & Potter J. D., 2010. Cardiac Troponin Mutations and Restrictive Cardiomyopathy. Journal of Biomedicine and Biotechnology, 2010: 350706.

Peddy S. B., Vricella L. A., Crosson J. E., Oswald G. L., Cohn R. D., Cameron D. E., Valle D., & Loeys B. I., 2006. Infantile restrictive cardiomyopathy resulting from a mutation in the cardiac troponin T gene. Pediatrics, 117(5): 1830–1833.

Rivenes S. M., Kearney D. L., Smith E. O. B., Towbin J. A., & Denfield S. W., 2015. Sudden death and cardiovascular collapse in children with restrictive cardiomyopathy. Circulation, 2015: 876–883.

Russo L. M., & Webber S. A., 2005. Idiopathic restrictive cardiomyopathy in children. Heart, 91: 1199–1202.

Seferovic P. M., Polovina M., Bauersachs J., Arad M., Gal T. B., Lund L. H., Felix S. B., Arbustini E., Caforio A. L. P., Farmakis D., Filippatos G. S., Gialafos E., Kanjuh V., Krljanac G., Limongelli G., Linhart A., Lyon A. R., Maksimovic R., Milicic D., Milinkovic I., Noutsias M., Oto A., Oto O., Pavlovic S. U., Piepoli M. F., Ristic A. D., Rosano G. M. C., Seggewiss H., Asanin M., Seferovic J. P., Ruschitzka F., Celutkiene J., Jaarsma T., Mueller C., Moura B., Hill L., Volterrani M., Lopatin Y., Metra M., Backs J., Mullens W., Chioncel O., de Boer R. A., Anker S., Rapezzi C., Coats A. J. S., & Tschope C., 2019. Heart failure in cardiomyopathies: a position paper from the Heart Failure Association of the European Society of Cardiology. European Journal of Heart Failure, 21(5): 553–576.

Takeda S., Yamashita A., Maeda K., & Maeda Y., 2003. Structure of the core domain of human cardiac troponin in the Ca(2₫)-saturated form. Nature, 424: 35–41.

Tariq M., 2014. Importance of genetic evaluation and testing in pediatric cardiomyopathy. World Journal of Cardiology, 6: 1156.

Ueno M., Takeda A., Yamazawa H., Takei K., Furukawa T., Suzuki Y., Chido-Nagai A., & Kimura A., 2021. A case report: Twin sisters with restrictive cardiomyopathy associated with rare mutations in the cardiac troponin I gene. Journal of Cardiology Cases, 23: 154–157.

Vallins W. J., Brand N. J., Dabhade N., Butler-Browne G., Yacoub M. H., & Barton P. J., 1990. Molecular cloning of human cardiac troponin I using polymerase chain reaction. FEBS Letters, 270: 57–61.

Van der Auwera G. A., Carneiro M. O., Hartl C., Poplin R., del Angel G., Levy-Moonshine A., Jordan T., Shakir K., Roazen D., Thibault J., Banks E., Garimella K. V., Altshuler D., Gabriel S., & DePristo M. A., 2013. From FastQ data to High-Confidence variant calls: The Genome Analysis Toolkit Best Practices Pipeline. Current Protocols in Bioinformatics, 43(1110): 11.10.1–11.10.33.

van den Wijngaard A., Volders P., Van Tintelen J. P., Jongbloed J. D., van den Berg M. P., Lekanne Deprez R. H., Mannens M. M. A. M., Hofmann N., Slegtenhorst M., Dooijes D., Michels M., Arens Y., Jongbloed R., & Smeets B. J. M., 2011. Recurrent and founder mutations in the Netherlands: cardiac troponin I (TNNI3) gene mutations as a cause of severe forms of hypertrophic and restrictive cardiomyopathy. Netherlands Heart Journal, 19: 344–351.

Wang G., Ji R., Zou W., Penny D. J., & Fan Y., 2017. Inherited cardiomyopathies: Genetics and clinical genetic testing. Cardiovascular Innovations and Applications, 2(2): 297–308.

Webber S. A., Lipshultz S. E., Sleeper L. A., Lu M., Wilkinson J. D., Addonizio L. J., Canter C. E., Colan S. D., Everitt M. D., Jefferies J. L., Kantor P. F., Lamour J. M., Margossian R., Pahl E., Rusconi P. G., & Towbin J. A., 2012. Outcomes of restrictive cardiomyopathy in childhood and the influence of phenotype: A report from the pediatric cardiomyopathy registry. Circulation, 126: 1237–1244.

Willott R. H., Gomes A. V., Chang A. N., Parvatiyar M. S., Pinto J. R., Potter J. D., 2010. Mutations in Troponin that cause HCM, DCM and RCM: what can we learn about thin filament function, Journal of Molecular and Cellular Cardiology, 48: 882–892.

Wittekind S. G., Ryan T. D., Gao Z., Zafar F., Czosek R. J., Chin C. W., & Jefferies J. L., 2019. Contemporary outcomes of pediatric restrictive cardiomyopathy: A single-center experience. Pediatric Cardiology, 40: 694–704.

Wong S., Feng H. Z., & Jin J. P., 2019. The evolutionarily conserved C-terminal peptide of troponin I is an independently configured regulatory structure to function as a myofilament Ca(2₫)-desensitizer. Journal of Molecular and Cellular Cardiology, 136: 42–52.

Xiaohui N., Min T., Ruohan C., Zhimin L., Keping C., & Shu Z., 2011. Predictors of prognosis in 107 patients with idiopathic restrictive cardiomyopathy. Heart, 97: A208–A209.




How to Cite

Lien, N. T. K., Nguyen, V. T., Le, T. T., Dang, T. H. V., Vu, Q. N., Nguyen, T. H., Do, M. H., Nguyen, H. L., Trinh, T. H., Nguyen, M. D., & Nguyen, H. H. (2024). Whole exome sequencing identifies variants in the \(\textit{TNNI3}\) gene in vietnamese patient with restrictive cardiomyopathy - a case report. Academia Journal of Biology, 46(1), 37–48. https://doi.org/10.15625/2615-9023/19255




Most read articles by the same author(s)