Novel frameshift mutation in Troponin C (TNNC1) associated with hypertrophic cardiomyopathy and sudden death

AbstractPurposeHypertrophic cardiomyopathy is the most common cause of sudden death in young people, including trained athletes, and is caused by mutations in genes encoding proteins of the cardiac sarcomere. Mutations in the Troponin C gene (TNNC1) are a rare genetic cause of hypertrophic cardiomyopathy. We describe a novel type of mutation (c.363dupG) in Troponin C, a rare form of hypertrophic cardiomyopathy.MethodsA family in which a 19-year-old asymptomatic male died of sudden cardiac death due to hypertrophic cardiomyopathy was genetically studied by sequencing 17 genes associated with hypertrophic cardiomyopathy or its phenocopies.ResultsA c.363dupG mutation in Troponin C was identified, and tested across the family.ConclusionsWe report the first frameshift mutation (c.363dupG or p.Gln122AlafsX30) in Troponin C causing hypertrophic cardiomyopathy (and sudden cardiac death) in a 19-year-old male, and have demonstrated that the mutation segregates with hypertrophic cardiomyopathy within the family.

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A Novel Mutation in TNNC1-ENCODED Cardiac Troponin C Predisposes to Hypertrophic Cardiomyopathy and Recurrent Episodes of Aborted Sudden Cardiac Death

Biophysical Journal ◽

10.1016/j.bpj.2010.12.832 ◽

2011 ◽

Vol 100 (3) ◽

pp. 114a

Author(s):

Michelle S. Parvatiyar ◽

Andrew P. Landstrom ◽

Jose Renato Pinto ◽

Jingsheng Liang ◽

Michael J. Ackerman ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Sudden Cardiac Death ◽

Cardiac Troponin ◽

Cardiac Death ◽

Novel Mutation ◽

Troponin C ◽

Cardiac Troponin C

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The Potential of Late Gadolinium Enhancement to Serve as a Predictor of Ventricular Arrhythmias in Hypertrophic Cardio-myopathy Patients

The Open Hypertension Journal ◽

10.2174/1876526201608010001 ◽

2016 ◽

Vol 8 (1) ◽

pp. 1-11

Author(s):

Thomas D. Gossios ◽

Georgios K. Efthimiadis ◽

Theodoros D. Karamitsos ◽

Thomas Zegkos ◽

Vasilios G. Athyros ◽

...

Keyword(s):

Late Gadolinium Enhancement ◽

Hypertrophic Cardiomyopathy ◽

Sudden Cardiac Death ◽

Sudden Death ◽

Cardiac Death ◽

Large Scale ◽

Small Subset ◽

Gadolinium Enhancement ◽

Inherited Cardiomyopathy ◽

Increased Risk

Hypertrophic cardiomyopathy, the most common inherited cardiomyopathy is well known to be the leading cause of sudden cardiac death in young people. However, amongst the population of patients, a small subset bears increased risk of sudden cardiac death and would benefit from implantation of a defibrillator, currently recognized utilizing a series of established risk factors. This risk stratification model is hampered by low positive predictive value. Therefore, novel predictors of sudden death are sought. The advent of cardiac magnetic resonance and late gadolinium enhancement has allowed accurate quantification of regional fibrosis, a key element of hypertrophic cardiomyopathy, pathophysiologically linked to increased arrhythmogenicity. We sought to review currently available data on the utility of late gadolinium enhancement to serve as a novel predictor of arrhythmias and sudden death. In conclusion, significantly diverse methodological approaches and subsequent findings between available studies on the topic have hampered such use, highlighting the need for uniformly designed large scale, prospective studies in order to clarify which aspects of myocardial fibrosis could serve as predictors of arrhythmic events.

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A novel KCNH2 frameshift mutation (c.46delG) associated with high risk of sudden death in a family with congenital long QT syndrome type 2

International Journal of Arrhythmia ◽

10.1186/s42444-020-00029-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Hyun Sok Yoo ◽

Nancy Medina ◽

María Alejandra von Wulffen ◽

Natalia Ciampi ◽

Analia Paolucci ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Long Qt Syndrome ◽

Cardiac Death ◽

Frameshift Mutation ◽

Alpha Subunit ◽

Syndrome Type ◽

Long Qt ◽

Qt Syndrome ◽

Congenital Long Qt Syndrome

Abstract Background The congenital long QT syndrome type 2 is caused by mutations in KCNH2 gene that encodes the alpha subunit of potassium channel Kv11.1. The carriers of the pathogenic variant of KCNH2 gene manifest a phenotype characterized by prolongation of QT interval and increased risk of sudden cardiac death due to life-threatening ventricular tachyarrhythmias. Results A family composed of 17 members with a family history of sudden death and recurrent syncopes was studied. The DNA of proband with clinical manifestations of long QT syndrome was analyzed using a massive DNA sequencer that included the following genes: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, ANK2, KCNJ2, CACNA1, CAV3, SCN1B, SCN4B, AKAP9, SNTA1, CALM1, KCNJ5, RYR2 and TRDN. DNA sequencing of proband identified a novel pathogenic variant of KCNH2 gene produced by a heterozygous frameshift mutation c.46delG, pAsp16Thrfs*44 resulting in the synthesis of a truncated alpha subunit of the Kv11.1 ion channel. Eight family members manifested the phenotype of long QT syndrome. The study of family segregation using Sanger sequencing revealed the identical variant in several members of the family with a positive phenotype. Conclusions The clinical and genetic findings of this family demonstrate that the novel frameshift mutation causing haploinsufficiency can result in a congenital long QT syndrome with a severe phenotypic manifestation and an elevated risk of sudden cardiac death.

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N-terminal pro-brain natriuretic peptide and sudden cardiac death in hypertrophic cardiomyopathy

Heart ◽

10.1136/heartjnl-2020-317701 ◽

2020 ◽

pp. heartjnl-2020-317701

Author(s):

Guixin Wu ◽

Jie Liu ◽

Shuiyun Wang ◽

Shiqin Yu ◽

Ce Zhang ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Sudden Cardiac Death ◽

Brain Natriuretic Peptide ◽

Natriuretic Peptide ◽

Cardiac Death ◽

Cardiac Fibrosis ◽

Discrimination Performance ◽

Net Reclassification Improvement ◽

C Statistic ◽

Increased Risk

ObjectiveElevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are associated with heart failure-related death in hypertrophic cardiomyopathy (HCM), but the relationship between NT-proBNP level and sudden cardiac death (SCD) in HCM remains undefined.MethodsThe study prospectively enrolled 977 unrelated patients with HCM with available NT-proBNP results who were prospectively enrolled and followed for 3.0±2.1 years. The Harrell’s C-statistic under the receiver operating characteristic curve was calculated to evaluate discrimination performance. A combination model was constructed by adding NT-proBNP tertiles to the HCM Risk-SCD model. The correlation between log NT-proBNP level and cardiac fibrosis as measured by late gadolinium enhancement (LGE) or Masson’s staining was analysed.ResultsDuring follow-up, 29 patients had SCD. Increased log NT-proBNP levels were associated with an increased risk of SCD events (adjusted HR 22.27, 95% CI 10.93 to 65.63, p<0.001). The C-statistic of NT-proBNP in predicting SCD events was 0.80 (p<0.001). The combined model significantly improved the predictive efficiency of the HCM Risk-SCD model from 0.72 to 0.81 (p<0.05), with a relative integrated discrimination improvement of 0.002 (p<0.001) and net reclassification improvement of 0.67 (p<0.001). Furthermore, log NT-proBNP levels were significantly correlated with cardiac fibrosis as detected either by LGE (r=0.257, p<0.001) or by Masson’s trichrome staining in the myocardium (r=0.198, p<0.05).ConclusionNT-proBNP is an independent predictor of SCD in patients with HCM and may help with risk stratification of this disease.

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Sudden Cardiac Death in Hereditary Dilated Cardiomyopathy

Sudden Cardiac Death ◽

10.5772/intechopen.91702 ◽

2020 ◽

Author(s):

Marianna Leopoulou ◽

Jo Ann LeQuang ◽

Joseph V. Pergolizzi ◽

Peter Magnusson

Keyword(s):

Sudden Cardiac Death ◽

Left Ventricle ◽

Sudden Death ◽

Risk Stratification ◽

Dilated Cardiomyopathy ◽

Cardiac Death ◽

Disease Risk ◽

Systolic Dysfunction ◽

Preventive Strategies ◽

Genetic Origin

Dilated cardiomyopathy (DCM) is characterized by the phenotype of a dilated left ventricle with systolic dysfunction. It is classified as hereditary when it is deemed of genetic origin; more than 50 genes are reported to be related to the condition. Symptoms include, among others, dyspnea, fatigue, arrhythmias, and syncope. Unfortunately, sudden cardiac death may be the first manifestation of the disease. Risk stratification regarding sudden death in hereditary DCM as well as preventive management poses a challenge due to the heterogeneity of the disease. The purpose of this chapter is to present the epidemiology, risk stratification, and preventive strategies of sudden cardiac death in hereditary DCM.

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