Background: Cardiomyopathies in children are serious, continuously progressing myocardium diseases which are characterized by a variety of the causes, symptoms, implications, and high lethality. More than 400 genes that can cause hereditary heart and vessels diseases are described in scientific literature. The application of a high-performance method of massive parallel sequencing allows to conduct the investigation of genome extended targeted areas revealing the variants and analyzing them (bioinformatics) for pathogenicity.Aims: Identification of a genetic etiology of hereditary cardiomyopathies development in children’s population of the Russian Federation.Materials and methods: The research included 103 patients with various phenotypes of cardiomyopathies aged from 3 months up to 17 years 9 months who at the moment of examination were observed in the cardiology department and the department of recovery treatment with cardiovascular diseases in the NMRCCH. All patients were performed massive parallel sequencing analyzing the targeted areas of 404 genes which mutations lead to the development of heart and vessels hereditary diseases.Results: The diagnostic algorithm based on the method of a massive parallel sequencing was developed. 176 258 minor options were identified in the explored target areas of genome of 103 patients. An average number of the revealed nucleotide replacements different from the reference sequence was 1711. We observed that about 40% of all variants founded by our means were found in MYH7, MYBPC3, TTN, MYH6, SCN5A, DSC2 and TPM1 genes. Bioinformatics analysis allowed revealing 68 novel genome variants associated with cardiomyopathy development. The reliable association of carriage of pathogenic option in MYBPC3 gene with development of hypertrophic cardiomyopathy in the Russian children was found.Conclusions: The application of the offered algorithm allowed establishing laboratory diagnoses to 99 (96.1%) patients out from 103 investigated subjects including the syndromal and non-syndromal forms of heart and vessels hereditary diseases which showed a cardiomyopathy phenotype.
Left ventricular non-compaction cardiomyopathy (LVNC) is a rare heart disease, with or without left ventricular dysfunction, which is characterized by a two-layer structure of the myocardium and an increased number of trabeculae. The study of familial forms of LVNC is helpful for risk prediction and genetic counseling of relatives. Here, we present a family consisting of three members with LVNC. Using a next-generation sequencing approach a combination of two (likely) pathogenic nonsense mutations DSG2-p.S363X and TBX20-p.D278X was identified in all three patients. TBX20 encodes the cardiac T-box transcription factor 20. DSG2 encodes desmoglein–2, which is part of the cardiac desmosomes and belongs to the cadherin family. Since the identified nonsense variant (DSG2-p.S363X) is localized in the extracellular domain of DSG2, we performed in vitro cell transfection experiments. These experiments revealed the absence of truncated DSG2 at the plasma membrane, supporting the pathogenic relevance of DSG2-p.S363X. In conclusion, we suggest that in the future, these findings might be helpful for genetic screening and counseling of patients with LVNC.
Background. Non-compaction cardiomyopathy is a group of genetically heterogeneous, poorly studied myocardial diseases with a variety of clinical manifestations (from asymptomatic course to progressive systolic dysfunction with symptoms of chronic heart failure, arrhythmias, and thromboembolic complications). Considering the variety of genetic disorders associated with the development of noncompaction cardiomyopathy, genetic verification of the diagnosis is important for determining the prognosis and conducting genetic counselling of families with cases of the disease.Description of the Clinical Case. The article presents two clinical observations of a severe course of non-compaction cardiomyopathy with remodeling of the heart cavities according to the dilated phenotype. In order to clarify the disease etiology, a molecular genetic study was conducted using the method of direct automatic sequencing with the analysis of targeted regions of 404 genes which mutations are described in hereditary diseases of the heart and blood vessels. After verifying the mutation (in the ACTC1 and MYBPC3 genes), we performed a search for the detected nucleotide substitution in the venous blood samples of parents and in one case — in the fetal DNA sample. The mode of inheritance has been determined; the probability of recurrence of the disease in siblings in subsequent pregnancies has been estimated.Conclusion. The description of clinical cases shows the importance of genetic verification of the diagnosis in patients with non-compaction cardiomyopathy for determining the disease prognosis and developing an algorithm for monitoring relatives of a proband.
The few foreign papers of the last decade have shown the relationship of various pathogenic variants of the ELAC2 gene to heterogeneous phenotypic manifestations, for which the unfavorable prognosis is common, caused by severe cardiomyopathy in the first year of life. The article presents the first clinical observation of a rare variant of the hypertrophic phenotype cardiomyopathy with a fatal outcome in the first year of life, and variants c.887T>C, p.L296P and c.1979A>T, p.K660I of the ELAC2 gene in Russia.The purpose of the work is to present clinical observation of a child with an early manifestation of a hypertrophic phenotype of cardiomyopathy caused by pathogenic variants of the ELAC2 gene.
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