Left ventricular noncompaction associated with titin-truncating variants in the TTN gene

Вахрушев, Ю А; Вершинина, Т. Л.; Федотов, П. А.; Kozyreva, Alexandra A; Kiselev, A. A.; Фомичева, Ю. В.; Васичкина, Е. С.; Pervunina, Tatiana; Kostareva, Anna

doi:10.15829/1560-4071-2020-4027

Russ J Cardiol

2020

DOI: 10.15829/1560-4071-2020-4027

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Left ventricular noncompaction associated with titin-truncating variants in the TTN gene

Ю А Вахрушев

Т. Л. Вершинина

П. А. Федотов

et al.

Abstract: Aim. To study the association of genetic variants in the titin gene (TTN) with the development and clinical course of left ventricular noncompaction in different age groups.Material and methods. The article discusses three clinical cases of patients with left ventricular noncompaction who were treated at theAlmazovNationalMedicalResearchCenter. We performed a new-generation sequencing of 108 genes associated with cardiomyopathies, as well as whole exome sequencing and Sanger sequencing.Results. We identified g… Show more

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Cited by 3 publications

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A clinical case of isolated non-compact left ventricular myocardium in a 29-year-old patient

Alieva,

Kovtyukh,

Teplova

et al. 2024

Russian Medicine

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Non-compact myocardium of the left ventricle is a rare heterogeneous pathology, which is based on the two-layer structure of the myocardium. One layer is formed by compact myocardium, the other layer is a spongy structure with multiple trabeculae and intertrabecular pouches communicating with the cavity of the left ventricle. Despite the fact that several different approaches to the diagnosis of non-compact myocardium of the left ventricle have been developed, there is no generally accepted definition of this form of pathology for both echocardiography and cardiac magnetic resonance imaging. This pathology can occur in any age group and is often asymptomatic. Due to the fact that the etiology and pathogenesis of non-compact myocardium of the left ventricle have not been fully studied, treatment of this disease to date remains nonspecific and symptomatic. In this publication, we present a description of the clinical case of a 29-year-old patient who was diagnosed with non-compact myocardium of the left ventricle. The disease debuted in the form of cardiac arrhythmia; according to the results of Holter monitoring, frequent ventricular extrasystole and atrioventricular block of the first and second degrees were registered. Echocardiography showed a decrease in left ventricular ejection fraction. The diagnosis was made after magnetic resonance imaging of the heart, which revealed the presence of non-compact myocardium of the anterior, lateral and inferior walls of the left ventricle in the apical and middle segments.

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A clinical case of isolated non-compact left ventricular myocardium in a 29-year-old patient

Alieva,

Kovtyukh,

Teplova

et al. 2024

Russian Medicine

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Spectrum of non-pathogenic variants in the titin gene and genes outside and intra-carcomeric cytoskeleton (TTN, MYBPC3, FLNC, RBM20) in patients with various variants of cardiomyopathy

Vakhrushev

Muravyov

Kozyreva

et al. 2022

Transl. med. (Print)

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Background. Sarcomere protein genes such as MYBPC3, FLNC, TTN, RBM20 are associated with cardiomyopathies (CMP). A large number of rare genetic variants complicates the interpretation genetic studies and assessing the pathogenicity. Moreover, there is a lack of an information about rare variants frequency in a healthy Russian population. Polymorphisms in these genes often act as modifiers, aggravating the clinical course of CMP caused by mutations in other genes.Objective. To compare the frequency of rare (less than 0.1 %) missense and truncating variants in the TTN, FLNC, MYBPC3, RBM20 genes in the patients with CMP and in the general population.Design and methods. The CMP group included 251 patients. The control group included 192 men (from the ESSE-RF study). A molecular genetic examination was performed using high-processive sequencing technology, followed by verification by Sanger sequencing.Results. The frequency of truncating variants in the genes TTN, FLNC, MYBPC3, RBM20 in the group with CMP was 7.17 %, and missense variants — 56.6 %: 11.5 % were pathogenic/likely pathogenic, 39.5 % — variants of uncertain significance, 49 % — probably benign/benign. The frequency of truncating variants in the TTN, FLNC, MYBPC3, RBM20 genes in the control group was 0.52 %, and the frequency of missense variants was 15.1 %: 38 % were variants of uncertain significance, 62 % — probably benign/benign.Conclusion. Frequency of missense and truncating variants with a frequency of less than 0.1 % in the TTN, FLNC, MYBPC3, RBM20 genes was increased in the group of patients with CMP.

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Features of the appearance of clinical cardiomyopathies against the background of truncating variants in the <i>ttn</i> gene: a review of the literature and an analysis of the appearance.

Vakhrushev,

Andreeva,

Gudkova

et al. 2023

Transl. med. (Print)

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Background. To date, the influence of genetic variants in the titin gene on the development of all types of cardiomyopathies has been proven, and this primarily applies to TTNtv, however, the high frequency of these variants in the control population (1–3 %) significantly complicates the determination of the pathogenicity of the detected variants. In addition, due to a significant population frequency (1–3 %) in patients with CMP, variants in the titin gene are often combined with causal variants in other genes, and thus can act as modifiers of the clinical course of the disease and myocardial remodeling.Objective. To study the effect of shortening variants in the titin gene on the clinical course of cardiomyopathies in the presence of causative variants in other genes or etiological factors of the disease.Design and methods. This article will consider three clinical cases of patients diagnosed with CMP who were treated at the Almazov National Medical Research Center. To conduct a genetic examination, next generation sequencing was used with a target cardiopanel to check 108 genes associated with the development of cardiomyopathies, as well as Sanger sequencing to exclude false positive results.Results. During a genetic examination of the studied patients, identified genetic variants in the titin gene led to the syn- thesis of a truncated protein: in all cases, the reason for this was frameshift deletions located in exons with a PSI (Percent Spliced-In) level of 100%. According to the American College of Medical Genetics and Genomics pathogenicity classification, two genetic variants are classified as pathogenic and one is classified as probably pathogenic.Conclusion. In these patients, we found shortening variants (frameshift deletions) in the titin gene, which acted as modifiers of myocardial remodeling.

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Left ventricular noncompaction associated with titin-truncating variants in the TTN gene

Cited by 3 publications

References 13 publications

A clinical case of isolated non-compact left ventricular myocardium in a 29-year-old patient

A clinical case of isolated non-compact left ventricular myocardium in a 29-year-old patient

Spectrum of non-pathogenic variants in the titin gene and genes outside and intra-carcomeric cytoskeleton (TTN, MYBPC3, FLNC, RBM20) in patients with various variants of cardiomyopathy

Features of the appearance of clinical cardiomyopathies against the background of truncating variants in the <i>ttn</i> gene: a review of the literature and an analysis of the appearance.

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