RBM20 (RNA-binding motif protein 20) is a splicing factor targeting multiple cardiac genes, and its mutations cause cardiomyopathies. Originally, RBM20 mutations were discovered to cause the development of dilated cardiomyopathy by erroneous splicing of the gene TTN (titin). Titin is a giant protein found in a structure of the sarcomere that functions as a molecular spring and provides a passive stiffness to the cardiomyocyte. Later, RBM20 mutations were also described in association with arrhythmogenic right ventricular cardiomyopathy and left ventricular noncompaction cardiomyopathy. Here, we present a clinical case of a rare arrhythmogenic phenotype and no structural cardiac abnormalities associated with a RBM20 genetic variant of uncertain significance.

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 genetic variants in the TTN gene leading to the synthesis of truncated protein: in the first two cases, the cause of noncompaction was a thirteen nucleotide deletion with a reading frame shift, in the second, a nonsense mutation. An algorithm for assessing the pathogenicity of the identified variants and a scheme of diagnostic genetic search are presented. Conclusion. Causal role of TTN -truncating variants in development of cardiomyopathies and, in particular, left ventricular noncompaction, requires a comprehensive clinical, segregation and bioinformatic analysis using international databases and the use of bioinformatics software.

Варианты в гене RBM20 у пациентов детского возраста с дилатационной кардиомиопатией

Aim. To study the prevalence of RBM20 gene polymorphisms and their relationship with the structural and functional left atrial (LA) characteristics in patients with coronary artery disease and heart failure with reduced ejection fraction (HFrEF).Material and methods. The study included 138 men aged 55,8±6,6 years with prior myocardial infarction ³12 months ago and HFrEF (class II-IV heart failure, left ventricular ejection fraction (Simpson’s methods), 25,1±7,2%). The control group consisted of 384 healthy donors. Genotyping of two RBM20 polymorphic variants (rs942077 and rs35141404) was performed by real-time polymerase chain reaction.Results. The prevalence of RBM20 polymorphisms did not differ in the HFrEF cohort and the control group. The GA rs35141404 genotype was more common among patients with a less pronounced increase in LA volume index (LAVI) (p=0,034). The minor A allele rs35141404 was associated with a protective effect on severe LA remodeling. However, this association did not reach the level of significance.Conclusion. For the rs942077 and rs35141404 polymorphic variants of the RBM20 gene, no significant associations were found with the LA size and atrial fibrillation presence in patients with HFrEF and old myocardial infarction. There was a tendency towards the association of the A allele and the GA rs35141404 genotype with a protective effect on LA remodeling. The data obtained confirm the need for further search for genotype-phenotype relationships of a wider population of patients with heart failure and coronary artery disease.

Background. Gene TTN associated with all types of cardiomyopathy, however its large size (294 b.p.) warrants a lot of individual unique genetic variants or variants with low frequency, that aggravates their interpretation. Besides that nowadays there is no data about spectrum of variants in this gene in healthy Russian population. Recognition frequency and spectrum of variants in gene TTN in healthy Russian population will allow us to use it for interpretation results of molecular genetic research for patients with different heart pathology, and define prognosis for different heart diseases.Objective. Recognize frequency and spectrum of single nucleotide and truncating variants in gene TTN in healthy Russian population and compare it with international data bases, and evaluate level of pathogenicity these variants and their distributing across titin structure.Design and methods. 192 men in age 55,8±6,6 years were tested with next-generation sequencing. Identified genetic variants were confirmed by Sanger sequencing. Results. Allele missense variant frequency (with frequency less than 0.1%) in TTN in healthy Russian population amount to 15.1 %, and truncating variants — 0.52 %. 37,9 % of them were variants of unknown significance, 62 % — likely-benign and 0.1 % — benign. There was no pathological and likely-pathological variants. Identified genetic variants distributed throughout the titin structure.Conclusion. Received result is congruent с international data bases and researches. Expended laboratory method (Next generation sequencing and confirmation with Sanger sequencing) can be used both in clinical practice, and in creating data bases of genetic variants in healthy Russian population.

Background: The molecular basis of myocarditis is often associated with genetic cardiomyopathies and truncating or loss-of-function variants in the titin gene (TTNtv/lof). Here, we hypothesize that titin serum levels increase in patients with myocarditis, and that this can depend on the genetic background of the disease. Methods: Forty-six patients with myocarditis were included in this study. Genotyping was performed using targeted panel sequencing. Serum titin levels and titin/creatinine ratios were measured in a subgroup of 27 patients. Results: Overall, 47 gene variants were identified, including 13 pathogenic and likely pathogenic variants and 34 variants of uncertain significance. The frequency of TTNtv/lof in patients with myocarditis was 11%. We detected significant differences between the TTNtv/lof group and the genotype-negative group in sustained ventricular tachycardia prevalence, myocardial reverse remodeling (∆ end-diastolic volume) and the prevalence of myocardial necrosis. Serum titin level was elevated in patients with myocarditis, negatively correlated with left ventricular ejection fraction, and was associated with ventricular arrhythmias and a low rate of myocardial reverse remodeling. Conclusions: In patients with biopsy-proven myocarditis, the rate of loss-of-function (LOF) variants was 28%, with a predominance of variants in structural and cytoskeletal genes, and TTNtv/lof variants were detected in 11% of patients. TTNtv/lof variant carriers were characterized by fewer morphological signs of inflammation and more favorable myocardial reverse remodeling. Serum titin levels were elevated in patients with myocarditis. Genotype-negative status of patients was characterized by the highest serum titin levels and titin/creatinine ratios, a lesser degree of myocardial reverse remodeling, sustained ventricular arrhythmias, and a larger area of necrosis.