Idiopathic dilated cardiomyopathy (DCM) is a common cardiomyopathy with the prevalence of 1:250, and at least one-third of all the cases are inherited. Mutations in the TTN gene are considered as the most frequent cause of inherited DCM and cover 10–30% of the cases. The studies were mainly focused on the adult or mixed age group of patients with DCM. The mutation rate in the TTN gene, the characteristics of manifestations and their prognostic significance in childhood have not been studied. To determine TTN mutation rate in children with DCM and the relevance of including this gene in the DNA diagnostic protocol for paediatric DCM, complete clinical and instrumental examination of 36 DCM patients (up to 18 years) with the manifestation of the disease was conducted in specialised cardiology centres. Molecular genetic testing included sequencing of coding and adjacent regulatory regions of the major cardiac TTN isoform N2BA using IonTorrent ™ semiconductor sequencing (for 25 isolated cases) and trio whole exome sequencing (trio WES)on the Illumina platform (for 11 family cases). Our pilot group included 36 probands with DCM diagnosis first established on the basis of the generally accepted criteria at the age of 5 days to 18 years(average age: 6.5 years). The sex ratio (M:F) was 23: 8. There were 25 sporadic DCM cases and 11 cases of familial DCM (at least one of the parents and/or siblings were also diagnosed with DCM). The only likely pathogenic truncating variant p.Arg33703*in the TTN gene (TTNtv) was found in a 16-year-oldmale proband out of 36 (3%). Apparently, TTN-dependent forms of DCMs manifest later at a young (but older than 18 years) or more mature age, and TTN gene cannot be considered as the first-line genetic testing for DCM in the paediatric group, despite several studies have reported a generally high mutation rate in this gene with DCM. Further research is needed to compare the representation of mutations in the TTN gene in different age groups of DCM patients.
Background: Brugada syndrome is a hereditary disease with genetic and phenotypic variability characterized by a high risk for arrhythmia and sudden cardiac death. It is assumed that modifying genetic factors contribute to the variability of the phenotype. Mitochondrial DNA (mtDNA) polymorphism can be considered among such factors, since mitochondrial dysfunction, including that associated with mtDNA variants, can have an arrhythmogenic effect. Aim: To study possible association between mtDNA polymorphism with the phenotype in the Russian patients with Brugada syndrome. Materials and methods: We have studied mtDNA polymorphism in 36 Russian probands with Brugada syndrome. Common “European” haplogroups of mtDNA were assigned using sequencing of the hypervariable segment 1 in mtDNA D-loop. Results: In the study sample, the frequencies of the mtDNA haplogroups generally correspond to the distribution common for the Russian populations, except the J haplogroup, which was not found in the studied probands. The results contradict with previously published data on the J and T haplogroups as risk factors for Brugada syndrome manifestation. Conclusion: The study did not reveal the role of mtDNA polymorphism (J and T haplogroups) in the formation of the Brugada syndrome phenotype.
Brugada syndrome (BrS) is an inherited disorder characterized by specific ST segment elevation in the right precordial leads, pseudo right bundle branch block, and a high risk of sudden cardiac death due to ventricular tachycardia. It was initially described as a monogenic disorder with an autosomal dominant mode of inheritance. It is hypothesized that modifying genetic factors, in addition to disease-causing mutations, may significantly contribute to the clinical symptoms and the risk of sudden cardiac death. These modifying factors can include mitochondrial DNA (mtDNA) variants. In particular, combination of mtDNA m.T4216C, m.A11251G, m.C15452A and m.T16126C variants (defining haplogroups T and J), is considered to be a factor that promotes manifestation of BrS manifestation, with no pro-arrhythmic effects. The aim of the present study was to confirm the reported association of BrS with MtDNA variants in a cohort of Russian patients. mtDNA haplogroups were genotyped in 47 Russian BrS probands and the prevalence of common mtDNA haplogroups was compared with the general population in European part of Russia. The distribution and prevalence of all but the J mtDNA haplogroups were comparable in BrS probands and the general Russian population. The mitochondrial J haplogroup was not found in the BrS cohort. In conclusion, it was shown that the mtDNA polymorphism, m.T4216C (haplogroups J and T) does not contribute significantly to the clinical manifestation of BrS in Russian patients.
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