A novel nonsense mutation in TNNT2 in a Chinese pedigree with hypertrophic cardiomyopathy

Gao, Guangyuan; Liu, Guohui; Chen, Weiwei; Tong, Yaliang; Mao, Cuiying; Liu, Jinsha; Zhang, Xing; He, Max M.; Yang, Ping

doi:10.1097/md.0000000000021843

Cited by 3 publications

(3 citation statements)

References 29 publications

(47 reference statements)

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“…The genetic locus of TNNT2 is 1q32.1 and its transcript contains 17 exons ( 11 ). The p.Arg92 codon within this gene has been described as a “hot spot” for mutation, and an p.Arg92Gln-TNNT2 pathogenic variant was determined to be the genetic culprit for the family in the current study.…”

Section: Discussionmentioning

confidence: 99%

“…Despite their genetic background, they presented with very different phenotypic manifestations of HCM, spanning clinical presentation, symptomatology, and cardiac imaging. This variable intra-familial phenotypic expressivity highlights the importance of genetic testing as a means of identifying susceptible individuals in families that carry HCM-causative genetic variants, especially considering most of the pathogenic mutations that cause HCM do not reliably predict clinical presentation, disease course, or prognosis ( 9 – 11 ). Furthermore, because of the vast phenotypic heterogeneity associated with HCM, many mutation carriers do not present with the typical finding of LVH and may be asymptomatic, going undiagnosed ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

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Tale of two hearts: a TNNT2 hypertrophic cardiomyopathy case report

Pham¹,

Giudicessi²,

Tweet³

et al. 2023

Front. Cardiovasc. Med.

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Hypertrophic cardiomyopathy (HCM) is a heritable cardiomyopathy that is predominantly caused by pathogenic mutations in sarcomeric proteins. Here we report two individuals, a mother and her daughter, both heterozygous carriers of the same HCM-causing mutation in cardiac Troponin T (TNNT2). Despite sharing an identical pathogenic variant, the two individuals had very different manifestations of the disease. While one patient presented with sudden cardiac death, recurrent tachyarrhythmia, and findings of massive left ventricular hypertrophy, the other patient manifested with extensive abnormal myocardial delayed enhancement despite normal ventricular wall thickness and has remained relatively asymptomatic. Recognition of the marked incomplete penetrance and variable expressivity possible in a single TNNT2-positive family has potential to guide HCM patient care.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tale of two hearts: a TNNT2 hypertrophic cardiomyopathy case report

Pham¹,

Giudicessi²,

Tweet³

et al. 2023

Front. Cardiovasc. Med.

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“…The TNNT2 gene (OMIM number * 191045) is known to encode the cardiac muscle-specific isoform of troponin T, which binds the troponin complex to tropomyosin in the thin filament of the sarcomere and regulates cardiac muscle contraction (Gao et al, 2020). The TNNT2 gene has 17 exons and is found on chromosome 1q32.1.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variation in Cardiac Troponin T Gene TNNT2 in Iraqi Patients with Cardiomyopathy

Mutlag¹,

Yenzeel²,

Subhi³

2022

PJMHS

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Cardiomyopathy is an affliction of the heart muscle that can result in heart failure.It comes in a variety of phenotypes, such as dilated, hypertrophic, and restricted. This study was aimed to investigate the polymorphism in cardiac Troponin T gene TNNT2 in Iraqi patients with cardiomyopathy. Eighty-two diagnosed cardiomyopathy adult patients with age range between (20-70) years, and thirty healthy with same range, were involved in this study during their attendance at Ibn Al- Bitar Center for Cardiac Surgery. The patients were diagnosed by an expert cardiologists based on ECG changes, Echocardiogram, chest x ray. The study was conducted from October 2020 to March 2021, and approved by ethical committees.: CSEC/0920/0052, September 15, 2020 of department of Biology, College of Science, University of Baghdad. Sequencing of the PCR products was performed by the genetic analyzer for forward and reverse primers in macrogen company (South korea), to detect the polymorphism in TNNT2 gene in cardiomyopathy patients. DNA was isolated from both groups (patients and control), and amplification of TNNT2 by using new set of primers to amplify 443 bp from (rs74315380, rs74315379) SNPs and 351bp from (rs3729547) SNP for being use in sequencing portion, and target SNPs will be involved in this region. The genotypes frequency of the rs3729547 SNP showed highly significant (p<0.001) different between patients and healthy group. Similarity, there is significant (p<0.05) differences among CC, TC and TT genotypes according to patients and healthy individuals. The SNP rs3729547 genotypes frequency in dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) showed significant (p<0.05) different between DCM and HCM patients related to TT genotypes, but not for CC and TC genotypes. Similarity, there is significant (p<0.05) different among CC, CT and TT genotypes according to DCM and HCM patients. Keywords: Cardiomyopathy, Troponin T, TNNT2 gene, rs74315380, rs74315379 and rs3729547.

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Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy

Topriceanu,

Pereira,

Moon

et al. 2024

Circulation

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Background: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease, as penetrance (proportion of G+ who develop disease) is variable, age-dependent, and not reliably predicted. Methods: A systematic search of the literature was performed. We employed random effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere genes in two different contexts: clinically-based studies on patients and families with HCM versus population/community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up. Results: 455 full text manuscripts were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in non-proband relatives carrying P/LP variants identified during cascade screening was 57% (95% confidence interval [CI] [52,63]) and the mean age of HCM diagnosis was 38 years (95% CI [36, 40]). Penetrance varied from ~32% for myosin light chain ( MYL3 ) to ~55% for myosin binding protein C ( MYBPC3 ), ~60% troponin T ( TNNT2 ) and troponin I ( TNNI3 ), and ~65% for myosin heavy chain ( MYH7 ). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population, but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower; approximatively 11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ~8 years of follow up, starting from a mean age of ~16 years. However, short-term gene-specific phenotypic conversion varied between ~12% for MYBPC3 to ~23% for MYH7 . Conclusions: The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve understanding of true lifetime penetrance in families and in the community, and to identify drivers of the transition from subclinical to overt HCM.

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A novel nonsense mutation in TNNT2 in a Chinese pedigree with hypertrophic cardiomyopathy

Abstract: Supplemental Digital Content is available in the text

Cited by 3 publications

References 29 publications

Tale of two hearts: a TNNT2 hypertrophic cardiomyopathy case report

Tale of two hearts: a TNNT2 hypertrophic cardiomyopathy case report

Genetic Variation in Cardiac Troponin T Gene TNNT2 in Iraqi Patients with Cardiomyopathy

Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy

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