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).

We report a novel variant in the MACF1 gene that caused a congenital brain anomaly (lissencephaly, brainstem hypoplasia, and agenesis of the corpus callosum) in a patient with severe neurodevelopmental delay and drug-resistant epilepsy. The patient was nonresponsive, nonverbal, and nonambulatory and experienced daily generalized myoclonic seizures, generalized muscle weakness, dysphagia, and faecal and urinary incontinence. Whole-exome sequencing revealed a missense heterozygous MACF1 variant, c.21878A>G (p.Asp7293Gly). The de novo origin of the variant was confrmed by trio Sanger sequencing. The variant was not reported previously in the gnomAD, ExAC, and 1000 Genomes databases. Our report expands the genetic heterogeneity of a rare type of lissencephaly.

Copy number variations of the human CNTN6 gene, resulting from megabase-scale microdeletions or microduplications in the 3p26.3 region, are frequently implicated in neurodevelopmental disorders such as intellectual disability and developmental delay. However, duplication of the full-length human CNTN6 gene presents with variable penetrance, resulting in phenotypes that range from neurodevelopmental disorders to no visible pathologies, even within the same family. Previously, we obtained a set of induced pluripotent stem cell lines derived from a patient with a CNTN6 gene duplication and from two healthy donors. Our findings demonstrated that CNTN6 expression in neurons carrying the duplication was significantly reduced. Additionally, the expression from the CNTN6 duplicated allele was markedly lower compared to the wild-type allele. Here, we first introduce a system for correcting megabase-scale duplications in induced pluripotent stem cells and secondly analyze the impact of this correction on CNTN6 gene expression. We showed that the deletion of one copy of the CNTN6 duplication did not affect the expression levels of the remaining allele in the neuronal cells.

Background: Chromosome 3q29 duplication syndrome is a rare chromosomal disorder with a frequency of 1:5000 in patients with a neurodevelopmental phenotype. The syndrome is characterized by phenotypic polymorphism and reduced penetrance. Methods: Patients were investigated by performing a cytogenetic analysis of GTG-banded metaphases, aCGH with the SurePrint G3 Human CGH Microarray 8×60K, qPCR, FISH, and WES. Results: Here, we report five new patients with atypical duplications overlapping with the 3q29 duplication syndrome region and no other genetic findings. In two patients, duplications were found in the single BDH1 gene, a candidate gene for the 3q29 duplication phenotype. For the first time, we delineated and described the smallest minimal critical region, including the single BDH1 gene; in our patients, this region was associated with ASD, heart defects, biliary tract dysfunction, and obesity. The frequencies of the pathological phenotypes in duplication carriers reported in the literature were calculated and compared with those in patients with 3q29 deletions. Most of the phenotypes were observed in both groups but were significantly less common among individuals with 3q29 duplications. Mirrored phenotypes in patients with duplications and deletions included overweight and weight deficit. Schizophrenia, generalized anxiety disorder, and recurrent ear infections were unique phenotypes of patients carrying deletions. Conclusion: Chromosome 3q29 duplication syndrome is characterized by a complex genetic architecture and clinical polymorphism.

Chromosomal aberrations, such as whole-chromosome aneuploidies (WCA), segmental aneuploidies (SA), whole-chromosome mosaicism (WCM), and segmental mosaicism (SM), are key factors influencing embryonic development and the outcomes of fertility programs. This analytic review critically examines the prevalence and origins of these genetic abnormalities, emphasizing the significant maternal contribution to WCA and the age-related nature of these aberrations. In contrast, SA, WCM, and SM appear largely age-independent and show considerable variability across studies, mainly due to technical artifacts and methodological differences. By analyzing the accumulated data, scrutinizing methodological discrepancies in preimplantation genetic testing for aneuploidies (PGT-A), and distinguishing between biological phenomena and artifacts, this review aims to clarify the current understanding of chromosomal aberrations in human embryos and their impact on reproductive health.

Whole exome sequencing of peripheral blood samples from Tuvan females diagnosed with breast and ovarian cancers (BC/OC) was performed to search for new genes involved in BC/OC pathogenesis. Considering the high cost of whole exome sequencing and study material requirements, 9 samples were selected from 61 genomic DNA samples. A mutation in the LGR4 gene (rs34804482) involved in the tumor-mediated Wnt signaling pathway and a mutation in the BRWD1 gene (rs147211854) involved in chromatin remodeling were identifed in BC patients. A mutation in the CITED2 gene (rs77963348) involved in the pathogenesis of primary ovarian insufciency was identifed in a patient with OC and a history of infertility. A mutation in the PDGFRA gene (rs2291591) was identifed in two BC/OC patients. LRG4, BRWD1, PDGFRA, and CITED2 germline pathogenic mutations were discovered in Tuvan women diagnosed with BC/OC for the frst time.

Our understanding of human genes – particularly their structure, functions, and regulatory mechanisms – is still limited. The biological role of approximately 20 % of human proteins has not been established yet, and the molecular functions of the known part of the proteome remain poorly understood. This hinders progress in basic and applied biological and medical sciences, especially in treating hereditary diseases, which are caused by mutations and polymorphic variants in individual genes. Therefore, it is crucial to comprehend the mechanisms of protein functioning to address this problem. This further emphasizes the importance of investigating gene functions and molecular pathogenetic pathways associated with single-gene inherited diseases. This review focuses on the TCF4 gene that encodes a transcription factor crucial for nervous system development and functioning. Pathogenic variants in this gene have been linked to a rare genetic disorder, Pitt–Hopkins syndrome, and TCF4 polymorphic variants are associated with several socially significant diseases, including various psychiatric disorders. The pathogenetic mechanisms of these conditions remain unexplored, and the knowledge about TCF4 upregulation and its target genes is limited. TCF4 can be expressed in various isoforms due to the complex structure and regulation of its gene, which complicates the investigation of the protein’s functions. Here, we consider the structure and functions of the TCF4 transcription factor. We discuss its potential target genes and the possible loss-of-function pathogenetic mechanisms identified in animal and cellular models of Pitt–Hopkins syndrome. The review also examines the advantages and limitations of potential therapies for Pitt–Hopkins syndrome that are based on TCF4 dosage compensation or altering the activity of TCF4 target genes.

Objective: To study the prevalence of chronic fatigue syndrome (CFS) and association of CFS with other clinical and neuropsychological manifestations of Parkinson's disease (PD) as well as with serum inflammatory markers and genetic polymorphisms.

Material and methods: The study included 533 patients with PD. All patients underwent clinical, neurological examination and neuropsychological testing using validated questionnaires: MoCA test, HADS, BDI-II, the Fatigue Severity Scale (FSS). Serum concentrations of inflammatory markers (slCAM-1, sVCAM-1, NCAM, CCL5, PAI-1 and MPO) were assessed in 144 patients using xMAP technology. A case-control study of CCL5 (rs2107538) and PAI-1 (rs2227631) gene polymorphisms was performed in connection with PD development and in groups differing in the presence/absence of CFS in PD. In addition, the relationship of these polymorphisms with variability in the levels of the corresponding proteins in the blood serum of patients was studied. Genotyping of CCL5 (rs2107538) and PAI-1 (rs2227631) polymorphisms was performed using real-time PCR with TaqMan probes.

Results: CFS is common in 66.7% of patients in the PD group. In addition, non-motor symptoms (emotional-affective, cognitive, autonomic disorders and pain) were more common in patients with CFS. A strong correlation has been established between the severity of CFS assessed with FSS and serum concentrations of CCL5, sVCAM-1, NCAM and slCAM-1. In newly diagnosed patients with PD who were not taking antiparkinsonian drugs at the time of the study and had CFS, higher correlations were noted between inflammatory markers and the severity of CFS manifestations. When comparing the distribution of genotypes and alleles of CCL5 (rs2107538) and PAI-1 (rs2227631) polymorphisms, some differences were found between the groups of patients with PD and controls (p<0.05). However, these polymorphisms did not affect the variability of serum protein levels CCL5 and PAI-1, respectively, nor did they affect the development of CFS in patients with PD.

Conclusion: CFS is common in PD, and patients with PD and CFS are characterized by elevated levels of serum markers CCL5, sVCAM-1, slCAM-1 and NCAM, suggesting the importance of the inflammatory component in the development of neurodegenerative disease. In addition, the clinical course of PD in patients with CFS is aggravated by other non-motor manifestations, including emotional-affective, cognitive, autonomic disorders and pain. These results highlight the potential contribution of an inflammatory component to the development of fatigue associated with PD, starting from the earliest clinical stages of the disease.

The transition of detached fragments of mitochondrial DNA into the nucleus and their integration into chromosomal DNA is a special kind of genetic variability that highlights the relation between the two genomes and their interaction in a eukaryotic cell. The human genome contains several hundreds of insertions of mtDNA fragments (NUMTS). This paper presents an overview of the current state of research in this area. To date, evidence has been obtained that the occurrence of new mtDNA insertions in the nuclear genome is a seldom but not exceptionally rare event. The integration of new mtDNA fragments into the nuclear genome occurs during double-strand DNA break repair through the non-homologous end joining mechanism. Along with evolutionarily stable “genetic fossils” that were integrated into the nuclear genome millions of years ago and are shared by many species, there are NUMTS that could be species-specific, polymorphic in a species, or “private”. Partial copies of mitochondrial DNA in the human nuclear genome can interfere with mtDNA during experimental studies of the mitochondrial genome, such as genotyping, heteroplasmy assessment, mtDNA methylation analysis, and mtDNA copy number estimation. In some cases, the insertion of multiple copies of the complete mitochondrial genome sequence may mimic paternal inheritance of mtDNA. The functional significance of NUMTS is poorly understood. For instance, they may be a source of variability for expression and splicing modulation. The role of NUMTS as a cause of hereditary diseases is negligible, since only a few cases of diseases caused by NUMTS have been described so far. In addition, NUMTS can serve as markers for evolutionary genetic studies. Of particular interest is the meaning of NUMTS in eukaryotic genome evolution. The constant flow of functionally inactive DNA sequences from mitochondria into the nucleus and its significance could be studied in view of the modern concepts of evolutionary theory suggesting non-adaptive complexity and the key role of stochastic processes in the formation of genomic structure.

. The Nivkhs are a small ethnic group indigenous of the Russian Far East, living in the Khabarovsk Territory and on Sakhalin Island, descending from the ancient inhabitants of these territories. In the Nivkhs, a specific Sakhalin-Amur anthropological type is prevalent. They are quite isolated, due to long isolation from contacts with other peoples. The gene pool of the Nivkhs and other Far Eastern and Siberian populations was characterized using a genome-wide panel of autosomal single-nucleotide polymorphic markers and Y chromosome haplogroups. Bioinformatic processing of frequencies of autosomal SNPs, Y chromosome haplogroups and YSTR haplotypes showed that the Nivkh gene pool is very different from the other populations’. Analysis of the SNP frequencies using the PCA method divided the Far Eastern populations in full accordance with the territories of their residence into the northern group of the Chukchi and Koryaks and the southern group, including the Nivkhs and Udege. The remoteness of the Nivkhs coincides with their geographic localization, with the Nivkhs and Udege demonstrating the greatest kinship. The Nivkhs have a specific component of their gene pool, which is present with much less frequency in the Udege and Transbaikal Evenks. According to the IBD blocks, the genotypes of the Nivkhs show a very small percentage of coincidence with the Udege, Koryaks, Evenks and Chukchi, the value of which is the lowest compared to the IBD blocks among all other Siberian populations. The Nivkh-specific composition of haplogroups and YSTR haplotypes was shown. In the Nivkhs, the C2a1 haplogroup is divided into three sublines, which have a fairly ancient origin and are associated with the ancestors of modern northern Mongoloids. The Nivkh haplogroup O2a1b1a2a-F238 is found among residents of China and Myanmar. The Q1a1a1-M120 line is represented among the Nivkhs, Koryaks, Evenks and Yukaghirs. Phylogenetic analysis of individual Y chromosomal haplogroups demonstrated the closeness of the Nivkh gene pool with the ancient population of the Amur and Okhotsk regions, the Koryaks, the Tungus peoples and the population of Southeast Asia. The Nivkh gene pool confirms the relative smallness of their ancestral groups without mixing with other populations.

Objective: To evaluate the frequency and severity of various clinical symptoms of Parkinson's disease (PD) depending on the BDNF rs6265 polymorphism.

Material and methods: The study included 533 patients with PD. The stage of PD was assessed using the Hoehn and Yahr scale (1967), motor symptoms were evaluated with MDS-UPDRS. Assessment of non-motor symptoms (NMS) in PD was conducted using the Beck Depression Inventory II (BDI-II); the Hospital Anxiety and Depression Scale (HADS); the Apathy Scale; the Montreal Cognitive Assessment (MoCA test); the Questionnaire for Impulsive-Compulsive Disorders in PD -Rating Scale (QUIP-RS). Genotyping of the BDNF variant (rs6265) was performed using real-time PCR with TaqMan probes.

Results: Most PD patients have a combination of NMS increasing as the disease progresses and is determined by molecular-genetic individual characteristics. There are significant differences in the severity of motor symptoms and NMS: individuals with the AA genotype showed significantly pronounced motor symptoms (p<0.0001); emotional-affective symptoms (p<0.0001); cognitive and impulsive behavioral disorders (p<0.0001).

Conclusion: The rs6265 BDNF allele A is associated with a wide range of NMS, increasing the risk of their development in patients with PD, thus playing the important role in the etiopathogenesis of this pathology.

BACKGROUND: The UBE2A protein belongs to the E2 family of ubiquitin-binding enzymes involved in the ubiquitination of substrate proteins. UBE2A mutations lead to congenital X-linked mental retardation syndrome-type Nascimento. How UBE2A participates in the central nervous system development is still unknown. AIM: To establish a cell model based on induced pluripotent stem cells (iPSCs) to study the molecular and cellular functions of UBE2A in neurogenesis. METHODS: Using genomic CRISPR-Cas9 editing and lentiviral transduction, a cell model based on iPSCs from two healthy donors was designed. This cell model includes isogenic iPSCs with knockout and inducible hyperexpression of UBE2A. In addition, iPSCs were obtained by reprogramming peripheral blood mononuclear cells of a patient diagnosed with X-linked mental retardation of Nascimento type, which has a deletion spanning the whole UBE2A locus. RESULTS: The obtained iPSCs demonstrate an ESC-like morphology. They express pluripotent cell markers OCT4, SOX2, SSEA-4, and TRA-1-81 and have normal karyotypes. iPSCs with UBE2A knockout or hyperexpression had significantly increased nuclei size compared with the isogenic control. CONCLUSION: The developed iPSC-based cell model can be used for fundamental studies of the functions of UBE2A in neurogenesis.

Проведен компонентный анализ состава генофондов коренных этносов Дагестана, а также других этносов Северного Кавказа и Центральной Азии на основе широкогеномного генотипирования SNP-маркеров на высокоплотных ДНК-микрочипах Infinium Multi-Ethnic Global-8. Анализ массива генотипических данных этнических популяций упомянутых выше регионов реализован в алгоритме Admixture (К = 12). Несмотря на то, что в этно-лингвистическом плане мегрелы относятся к народности картвельской языковой семьи, абхазы, адыги и черкесы принадлежат к группе этносов абхазо-адыгских языков, осетины, являются ираноязычным этносом, а карачаевцы и балкарцы представляют тюркскую группу народов Северного Кавказа, все перечисленные этносы имеют спектр одних и тех же предковых компонент, к тому же в сопоставимых пропорциях. Ингуши и чеченцы, будучи представителями нахской группы нахско-дагестанской языковой семьи, демонстрируют одну общую предковую компоненту с высокой степенью представленности, подчеркивающую обособленную генетическую историю формирования их генофонда. Караногайцы Дагестана и ногайцы из Карачаево-Черкесии по спектру и частоте представленности предковых компонент указывают на общность с центрально-азиатскими этносами, такими как казахи и узбеки. Этносы Дагестана демонстрируют уникальную картину разнообразия как состава, так и частоты встречаемости предковых компонент в структуре их аутосомного генофонда. Это подчеркивает не только обособленную от других народов Северного Кавказа историю их формирования, но и длительно изолированную собственную генетическую историю каждого коренного этноса. Исследование находится в рамках фундаментальных направлений популяционной и эволюционной генетики человека – выявления этноспецифичных особенностей структуры геномов и популяционных генофондов современных популяций человека, реконструкции древних миграций и экспансии численности населения, а также эволюции генофондов и механизмов генетической адаптации.

Rare pathogenic variants in genes whose protein products form the structure of the extracellular matrix, regulate smooth muscle cell function, or belong to the TGFβ/SMAD signaling pathway are detected in 20–30% of thoracic aortic aneurysm (TAA) cases. In addition to the structural changes, epigenetic events associated with these genes may influence the risk of aortic aneurysm. This review summarizes the published study results on the functional significance of epigenetic modifications in the genes of Mendelian forms of TAA. Most TAA genes are characterized by overlapping localization with genomic noncoding regulatory elements (including genes of microRNAs, long noncoding RNAs, etc.). These genomic regions have not been practically studied in patients with aortic aneurysm, but a number of noncoding RNAs (ACTA2-AS1, TGFB2-AS1, PRKG1-AS1) have been shown to be involved in the regulation of processes pathogenetically significant for aortic aneurysm (proliferation, apoptosis, autophagy, inflammation, endothelial dysfunction) and metabolic pathways (TGFβ/SMAD, Wnt/β-catenin). In the regions of TAA genes, the changes in DNA methylation are also recorded both in the presence of risk factors (structural features of the aorta, blood flow patterns) and in the development of aortic aneurysm. Various epigenetic events may also exert the pathogenic effects of aortic aneurysm-associated genetic variants localized in TAA genes. Thus, despite the fact that the long noncoding RNA and microRNA genes located in the TAA gene region and various epigenetic events (including histone modifications and DNA methylation) have not been sufficiently studied in this aortopathy, the information provided in scientific publications allows us to consider these epigenetic markers as promising regulators of certain pathogenetic processes in the development of an aortic aneurysm.