НИИ
медицинской
генетики

The goal of this study was to analyze copy number variations (CNVs) in spontaneous abortions with a euploid karyotype, irrespective of the method used for CNV detection. This systematic review was performed in accordance with the PRISMA guidelines. Articles published between 2006 and 2023 were selected through the PubMed database. Studies were included if they involved CNV analysis in spontaneous abortions using any CNV detection method. The pathogenic significance of CNVs was interpreted based on the American College of Medical Genetics and Genomics (ACMG) guidelines. Nineteen publications met the inclusion criteria. A total of 1425 CNVs were identified in 550 samples from 3953 euploid spontaneous abortions, representing 14% of the cases. Among the detected CNVs, 9% were classified as pathogenic, and 7.5% were likely pathogenic. The most frequently observed pathogenic CNVs included 22q11.2 deletion/duplication, 16p13.11 deletion, 15q11.2 deletion/duplication, 1p36.33 duplication, and 17p13.3 duplication. The genomic regions with the highest frequency of CNVs, regardless of their pathogenic effect, were 8q24.3, 16p13.3, 21q22.3, Xp22.33, Xp22.31, and Xq28. No clear associations were found between specific CNVs and pregnancy loss. However, deletions in the 22q11.2 region emerged as the most likely candidates contributing to lethality during the early stages of embryonic development.

Ischemic heart disease (IHD) is an important medical and social problem. ST-elevation myocardial infarction (STEMI) is the most severe form of IHD, affecting all layers of the heart muscle. One of the diagnostic criteria for endothe lial dysfunction in myocardial infarction is the level of sE selectin, a cell adhesion molecule that recruits neutrophils and induces neutrophil inflammation. The aim of this study is to investigate intronic polymorphisms rs5353, rs3917412 and rs1534904 of the E-selectin coding gene SELE in patients with STEMI. We have analyzed a group of patients with STEMI (n = 74) and a population sample of Tomsk (n = 136) as the control group. The frequencies of the rs5353 genotypes in the SELE gene have shown statistically significant differences between patients and the control sample (p = 0.004). The CC genotype is a predisposing factor to STEMI (OR = 6.93, CI:95 % (1.84–26.04), χ2 = 8.69, p = 0.002). The analyzed markers were not studied previously in cardiovascular diseases (CVDs) and were rarely involved in association studies at all; there is no information on these SNPs in the leading databases. At the same time, all three variants, according to the RegulomeDB classification, belong to the functional class 1f, and are highly likely to have regulatory potential rela tive not only to the SELE gene, but also to other genes in the nearby region. The analysis of the functional significance of the studied markers has shown the presence of a region more extensive than one gene, which is co-regulated by the studied nucleotide substitutions. The association of rs5353 with STEMI identified in this study once again confirms the involvement of the SELE gene in the pathogenesis of CVDs. It is possible that this entire region of the genome may be involved indirectly in the pathogenesis of CVD through the systems of inflammation, immune response and DNA repair.

Aortic aneurysm (AA) and atherosclerosis (AS) of various vascular beds are asymptomatic for a long time and are relatively common pathological conditions that lead to life-threatening and disabling complications. In this review, we discuss the current understanding of the high variation in direct and inverse comorbidity of AA and AS as presented in scientific publications. Estimates of AA and AS comorbidity depend on several factors, such as the location of AA (ascending or descending thoracic aorta or abdominal aorta), familial or sporadic cases of AA, syndromic forms of AA, and/or aortic valve pathology (bicuspid aortic valve [BAV]). To identify the causes of the comorbidity of AA and AS, it is important to consider and characterise many factors in detail. These factors include clinical characteristics of the patients included in a study (age, sex) and risk factors (mainly the presence of monogenic forms and BAV, hypertension, hypercholesterolaemia, diabetes mellitus, and cigarette smoking). Additionally, it is essential to consider characteristics of the disease course and the nature of multimorbidity and to take into account pathologies not only of the cardiovascular system but also of other organ systems, with special attention to metabolic and endocrine disorders.

Background: The X chromosome is enriched with genes related to brain development, and the hemizygous state of these genes in men causes some difficulties in the clinical interpretation of copy number variations (CNVs). In this study, we present data on the frequency and spectrum of CNVs on the X chromosome in a cohort of patients with neurodevelopmental disorders (NDDs).
Methods: Chromosomal microarray analysis was performed for 1175 patients with NDDs. CNVs were confirmed by real-time quantitative PCR. X chromosome inactivation was analysed by methyl-sensitive PCR. To determine the pathogenic significance of the CNVs, several criteria, including the origin (inherited or de novo), variant type (microdeletion or microduplication), and X chromosome inactivation pattern in asymptomatic and symptomatic carriers, were considered. Additionally, the spectrum, size and molecular bases of copy number changes in genes or gene regions involved in the development of the pathological phenotype in each patient were considered.
Results: CNVs on the X chromosome were identified in 33 patients (2.8%). Duplications and triplications (27 cases) were four times more common than deletions (6 cases). In 74% of patients, CNVs were of maternal origin; in 10% they were of paternal origin; and in 16% they arose de novo. The frequency of skewed X inactivation among family members who were healthy carriers of pathogenic and likely pathogenic CNVs and variants of uncertain significance (VUSs) on the X chromosome was 23%. For the first time, we reported several CNVs, including a pathogenic microdeletion at Xq26.1q26.2 involving the ARHGAP36 gene and a microduplication at Xp22.2 involving the OFD1 gene, CONCLUSIONS: This study expands on the frequency and spectrum of CNVs in patients with NDDs. Pathogenic variants on the X chromosome were present in 15% of cases, LP in 12%, VUS in 57%, and LB in 16% of cases. Previously unreported CNVs aid in the identification of new structural variants and genes associated with X-linked intellectual disability. We propose to consider the X-chromosome inactivation status when assessing the pathogenetic significance of CNVs using the ACMG algorithm (American College of Medical Genetics).