Sotos syndrome is a rare autosomal dominant disorder with an incidence of about 1 in 14,000 newborns. Despite a number of characteristic clinical manifestations, its diagnosis is difficult due to the high degree of overlap of the phenotype with a number of other hereditary syndromes, such as Beckwith-Wiedemann syndrome or Marfan syndrome. The molecular genetic cause of Sotos syndrome is mutations in the NSD1 gene, leading to protein dysfunction. The article presents and characterizes variants in the NSD1 gene found during diagnostics using high-throughput sequencing (NGS) and MLPA.

Aim: to evaluate changes in the methylation status of cytosine residues in CpG islands, monoallelically methylated in the norm, in samples of malignant breast tumors. Methods. To determine CpG dinucleotides monoallelically methylated in tumor and normal breast tissues, we used the results of Xmal-RRBS genome-wide bisulfite sequencing obtained earlier. Changes in monoallelic methylation in tumors were visualized using histograms for different breast methylotypes. Results. In the genomes of moderately methylated tumors, normally methylated CpG dinucleotides have a tendency to an almost equiprobable methylation change to both the unmethylated and fully methylated states. In the genomes of hypermethylated tumors, normally monoallelically methylated CpG dinucleotides more often change their state to fully methylated. Conclusions. The observed nature of the changes suggests that the dynamics is dictated in moderately methylated tumors by processes that do not determine their vector, and in hypermethylated tumors, additionally, by a directed process that increases the methylation level of CpG dinucleotides. By analogy with the previously published results of a study of the dynamics of changes in methylation of imprinted loci in human tumors, we assume that the process of random determination of the vector of methylation changes is mediated by copy number aberrations at the regions of monoallelic DNA methylation. The reason for the equally probable bidirectional changes in monoallelic methylation may be a genomic imbalance that can randomly lead to deletions (or acquired uniparental disomy) of either the methylated or unmethylated allele.

Gastric cancer (GC) is one of the significant causes of mortality from cancer. An unfavorable forecast for GC is largely associated with tumor metastasis. Expression of genes and microRNAs can be a source of biomarkers that signal the increased risk of tumor metastasis. The detection of genes associated with tumor metastasis, and the creation of a candidate prognostic panel of microRNAs and genes is very relevant. We investigated the expression of MIR-34A and MIR -335 microRNA and FGFR2, VEGFR1 and NRP1 genes with disseminated gastric cancer in comparison with non-metastatic GC tumors. Association is characterized with the development of remote metastasis, indicating their quality as candidates for markers. Panels are formed, including genes, and microRNAs - candidates for prognostic markers. A comparative analysis of the panels allowed to be characterized as the most efficient panel, including MIR335/VEGFR1/FGFR2, which demonstrates the best indicators as a candidate for the metastasis prediction panel, especially the value of the ratio of the chance of OR = 143 and RR = 7.1.

Background. TLR-mediated activation of the innate immune response varies with cell type. TLRs can recognize not only exogenous pathogenic molecules (PAMP - pathogen-associated molecular patterns), but also endogenous molecules that appear during tissue damage, aseptic inflammation, and degeneration - DAMP. Under certain circumstances, this reaction may be uncontrollable, which leads to the development of severe systemic inflammation and sepsis. TLR9 is the only TLR that is capable of detecting pathogenic CpG DNA in endolysosomal structures. GC-rich rDNA fragments, which are TLR9 ligands, are accumulated in eDNA during pathology, pregnancy, or under the action of damaging factors. Aim: to investigate the influence of cfDNA fragments of different composition on the expression of TLR9 and on the expression of other human TLRs in in vitro cultures. Methods. The study was carried out on histologically different cultures with different proliferative potentials: mesenchymal stem cells (N = 13), HUVEC (N = 7), and MCF7 human breast adenocarcinoma cells. The expression of surface proteins by cells was studied by flow cytometry. To simulate the effect of eDNA on different types of cells, there were prepared model forms of DNA: genomic DNA (hydrolyzed by nuclease), oxidized forms of gDNA, and a model GC-enriched DNA fragment - CpG - a rich fragment of the transcribed region of rDNA. The expression level of TLR 1-10 genes was assessed by real-time PCR. Results. We noticed an increase in the expression of intracellular endoplasmic receptors TLR3, TLR7 and TLR8 genes in response to the action of both GC-rich and oxidized cfDNA fragments in different types of cells. In addition, the presence of cfDNA increases the expression of cell surface receptors TLR6 genes, and, to a lesser extent, TLR1 and TLR5. Under the action of oxidized fragments, the expression of the TLR4 gene increases. However, an increase in the expression of TLR family genes occurs secondarily after TLR9 activation. Blocking TLR9 inhibits signal transduction through other TLRs. Conclusions. Binding of An increase in the expression of receptors of the TLR family, except for TLR9, observed upon exposure to cfDNA, may be associated with the involvement of the TLR network in the regulation of signal transduction through TLR9, both through interactions between TLR receptors and through other signaling pathways associated with cfDNA recognition by DNA sensors.

Background. About 40-50% of male infertility cases are due to pathozoospermia. Assessment of gene - gene interactions associated with pathospermia is an important task. Aim: to analyze the intergenic interactions of PON1 (Q192R), SOD1 (G7958A), CAT (C262T), NOS3 (C786T) and hOGG1 (Ser326Cys) polymorphisms in pathozoospermia. Methods. The study included 130 residents of the Rostov region. The comparison group consisted of 80 men with pathospermia, aged 23 to 48 years. The control group was formed from 50 sperm donors, collaborated with «The center of human reproduction and IVF». Determination of SNP was carried out using allele-specific polymerase chain reaction. Differences in the distribution of allelic variants of genes in the examined groups were assessed using the χ2 criterion. The risk of developing pathozoospermia was judged by the odds ratio. Modeling of intergenic interactions of polymorphic loci of PON1, SOD1, NOS3, CAT, hOGG1 genes was performed using the Multifactor Dimensionality Reduction software. Results. As a result of the study, the frequencies of genotypes and alleles were determined for polymorphic variants of the genes of enzymes involved in free radical processes in men with pathozoospermia. A significant model of intergenic interactions of polymorphic loci of the studied genes was revealed, affecting the risk of developing pathozoospermia, characterized by a cross-validation coefficient of 10/10 and a prediction accuracy of 78% (χ2 = 36.74 (p <0.0001), OR = 12.27, 95% CI 5.09 - 29.55). Conclusions. As a result of the analysis of intergenic interactions of polymorphic variants of the PON1, SOD1, NOS3, CAT, hOGG1 genes in the development of pathozoospermia using the Multifactor Dimensionality Reduction method, statistically significant associations were found that lead to an increase in the risk of developing this pathology.

Epidermolysis bullosa (EB) is the group of rare genodermatoses and is characterized by high genetic heterogeneity. The article presents the first results of the examination of 305 Russian patients with epidermolysis bullosa. The 217 genetic variants were identified in 8 genes - KRT5, KRT14, KLHL24, COL17A1, LAMB3, COL7A1, FERMT1, TGM5. The 96 (44.2%) variants from the 217 were identified for the first time. The genetic diversity of the identified variants in different clinical types of EB is considered.