Contactin 6 (CNTN6) is a recently discovered member of the contactins family, which belongs to a group of cell adhesion molecules. This review summarizes the current knowledge about the possible functions of CNTN6 in the organism and its manifestations in animal models and human diseases. Histological, cellular, and molecular studies in rodents have shown the involvement of this protein in neurite guidance, neural network development, and oligodendrocytogenesis. The expression levels in the cerebellum, hippocampus, and visual cortex of rodents vary depending on the period of neurodevelopment. Animal models with a deletion of the Cntn6 gene have shown impaired spatial orientation and memory patterns. In humans, copy number variation (CNV) analysis and genome-wide association studies (GWAS) found allele-phenotype relationship of this gene with autism spectrum disorder (ASD), intellectual disability (ID), Tourette syndrome (TS), schizophrenia (SCZ), anorexia, and other mental and neurodevelopmental diseases.

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).

Chromosomal abnormalities in human pre-implantation embryos, originating from either meiotic or mitotic errors, present a significant challenge in reproductive biology. Complete aneuploidy is primarily linked to errors during the resumption of meiosis in oocyte maturation, which increase with maternal age, while mosaic aneuploidies result from mitotic errors after fertilization. The biological causes of these abnormalities are increasingly becoming a topic of interest for research groups and clinical specialists. This review explores the intricate processes of meiotic and early mitotic divisions in embryos, shedding light on the mechanisms that lead to changes in chromosome number in daughter cells. Key factors in meiotic division include difficulties in spindle assembly without centrosomes, kinetochore (KT) orientation disturbances, and inefficient cell-cycle checkpoints. The weakening of cohesion molecules that bind chromosomes, exacerbated by maternal aging, further complicates chromosomal segregation. Mitotic errors in early development are influenced by defects in sperm centrosomes, KT misalignment, and the gradual depletion of maternal regulatory factors. Coupled with the inactive or partially active embryonic genome, this depletion increases the likelihood of chromosomal aberrations. While various theoretical mechanisms for these abnormalities exist, current data remain insufficient to determine their exact contributions. Continued research is essential to unravel these complex processes and improve outcomes in assisted reproductive technologies.

This review article aims to summarize the existing concepts related to embryoid bodies (EBs) and explore their potential as a model system for studying various aspects of human embryonic development. The review involves the collection and analysis of information about the characteristics of EBs and the properties of stem cells that give rise to them. The results show that EBs derived from pluripotent stem cells are a promising model that closely replicates processes occurring in human embryos after implantation. The review also provides a comparative analysis of the advantages and limitations of models based on induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), with particular attention given to summarizing the results of limited studies on RNA sequencing in individual cells from human and mouse EBs. In conclusion, we would like to emphasize that embryoid bodies are an effective model system for studying early human embryogenesis. This opens up new possibilities for reproductive genetics and medicine.

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

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 confirmed 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.

The purpose of this study was to identify genes in the placenta of monosomy X embryos whose methylation abnormalities may be associated with embryonic death. Methylation levels were assessed via reduced representation bisulfite sequencing of the chorionic villi of embryos from 8 spontaneous abortions during the first trimester of pregnancy with the 45,X karyotype and 7 embryos from medical abortions with the 46,XX and 46,XY karyotypes. The methylation levels of several identified differentially methylated genes were analyzed in 22 embryos from spontaneous abortions with monosomy X compared with 11 embryos from medical abortions using targeted bisulfite massive parallel sequencing. Compared with embryos with 46,XX and 46,XY karyotypes, respectively, differentially methylated CpG sites in embryos with monosomy X were located in 831 and 254 differentially methylated genes (DMGs). However, only 74 DMGs were unique for 45,X embryos after subtraction of the DMG of spontaneously aborted embryos with a normal karyotype (n = 4). Compared with embryos of both sexes, 48 genes in embryos with monosomy X were differentially methylated, 21 of which are important in normal placental and embryonic development and whose dysregulation is linked to preeclampsia and embryonic death. Targeted analysis confirmed that the ALCAM gene is hypermethylated and that the BDH1 gene is hypomethylated in embryos with monosomy X. Aberrant methylation of genes involved in placentation, proliferation, and cell differentiation has been detected in spontaneously aborted embryos with monosomy X. These disorders may be associated with the high lethality of embryos with monosomy X.

BACKGROUND:Effective molecular diagnosis of congenital diseases hinges on comprehensive genomic analysis, traditionally reliant on various methodologies specific to each variant type-whole exome or genome sequencing for single nucleotide variants (SNVs), array CGH for copy-number variants (CNVs), and microscopy for structural variants (SVs). METHODS:We introduce a novel, integrative approach combining exome sequencing with chromosome conformation capture, termed Exo-C. This method enables the concurrent identification of SNVs in clinically relevant genes and SVs across the genome and allows analysis of heterozygous and mosaic carriers. Enhanced with targeted long-read sequencing, Exo-C evolves into a cost-efficient solution capable of resolving complex SVs at base-pair accuracy. RESULTS:Applied to 66 human samples Exo-C achieved 100% recall and 73% precision in detecting chromosomal translocations and SNVs. We further benchmarked its performance for inversions and CNVs and demonstrated its utility in detecting mosaic SVs and resolving diagnostically challenging cases. CONCLUSIONS:Through several case studies, we demonstrate how Exo-C's multifaceted application can effectively uncover diverse causative variants and elucidate disease mechanisms in patients with rare disorders.

Pregnancy loss is the most common obstetric complication occurring in almost 15

The level of chromosomal abnormalities in the somatic cells of adult individuals is characterized by significant interindividual variability, which may be partly affected by the genetic and epigenetic background. The epigenetic landscape in cells is largely determined by genome methylation. This study aimed to analyse the relationships between global genome methylation and the frequencies of chromosome abnormalities in lymphocytes of plutonium workers. The frequencies of chromosome aberrations, micronuclei, aneuploidy of chromosomes 2, 7, 8, 12, X and Y and sister chromatid exchanges were analysed in the lymphocytes of 40 male workers from a nuclear chemical facility (Seversk, Russia) with incorporated plutonium-239 and 49 healthy male volunteers who had no occupational exposure to ionizing radiation. The long interspersed nuclear elements-1 (LINE-1) methylation index was assessed as a well-known marker of global genome methylation. The frequencies of centromere-negative micronuclei (4.74 ± 2.26‰ vs. 3.02 ± 1.69‰), chromosome-type aberrations (0.81 ± 0.79 vs. 0.44 ± 0.69%) and total chromosome non-disjunction (0.93 ± 0.43 vs. 0.50 ± 0.25%) were significantly higher in the group of workers than in controls (p 0.05). The LINE-1 methylation index did not differ significantly between the worker and control groups (74.93 ± 3.63 vs. 73.92 ± 4.62%). Correlations between LINE-1 methylation and the frequency of micronuclei (R = –0.35, p = 0.031) were observed in the control group, whereas correlations of LINE-1 methylation with chromatid-type aberrations (R = –0.42, p = 0.012) (but not chromosome-type aberrations) and with sister chromatid exchanges (R = –0.53, p = 0.004) were observed only in the group of plutonium workers. Thus, LINE-1 hypomethylation after plutonium exposure is associated mainly with chromatid breaks, either repaired or misrepaired.

Сочетание инвертированной дупликации с терминальной делецией 8р (invdupdel(8p)) – редкая хромосомная перестройка, проявляющаяся задержкой нейропсихического развития, умственной отсталостью, пороками сердца и аномалиями мозга. Известно, что полиморфная парацентрическая инверсия в структуре хромосомы 8 матери может привести к перестройке invdupdel(8р) у ее ребенка. Нами создана система зондов для поиска FISH-методом скрытой инверсии в хромосоме 8 матери пациента с задержкой развития, гипотонией, черепно-лицевыми аномалиями и кольцевой хромосомой 8, обусловленной invdupdel(8р). Инверсия в структуре хромосомы 8 у женщины выявлена, что указывает на необходимость проведения пренатальной диагностики при наступлении беременности. The combination of an inverted duplication with a terminal 8p deletion (invdupdel(8p)) is a rare chromosomal rearrangement that manifests with neurodevelopmental delay, intellectual disability, heart defects, and brain abnormalities. It is known that a polymorphic paracentric inversion in the structure of mother’s chromosome 8 can lead to invdupdel(8p) in her child. We have created a system of DNA-probes to search with the FISH-method for cryptic inversion in chromosome 8 of the mother of a patient with developmental delay, muscle hypotonia, craniofacial anomalies and ring chromosome 8 caused by invdupdel(8p). An inversion in the structure of chromosome 8 in a woman was revealed, which indicates the need for prenatal diagnosis in the case of pregnancy.

An information-analytical software has been developed for creating digital models of structures of porous materials. The information-analytical software allows you to select a model that accurately reproduces structures of porous materials—aerogels—creating a digital model by which you can predict their properties. In addition, the software contains models for calculating various properties of aerogels based on their structure, such as pore size distribution and mechanical properties. Models have been implemented that allow the description of various processes in porous structures—hydrodynamics of multicomponent systems, heat and mass transfer processes, dissolution, sorption and desorption. With the models implemented in this software, various digital models for different types of aerogels can be developed. As a comparison parameter, pore size distribution is chosen. Deviation of the calculated pore size distribution curves from the experimental ones does not exceed 15%, which indicates that the obtained digital model corresponds to the experimental sample. The software contains both the existing models that are used for porous structures modeling and the original models that were developed for different studied aerogels and processes, such as the dissolution of active pharmaceutical ingredients and mass transportation in porous media.

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.

In humans, aneuploidy is incompatible with the birth of healthy children and mainly leads to the death of embryos in the early stages of development in the first trimester of pregnancy. Trisomy 16 is the most common aneup loidy among spontaneous abortions of the first trimester of pregnancy. However, the mechanisms leading to the death of embryos with trisomy 16 remain insufficiently investigated. One of these potential mechanisms is abnormal placental development, including aberrant remodeling of spiral arteries. Spiral artery remodeling involves the migration of trophoblast cells into the maternal spiral arteries, replacing their endothelium and remodeling to ensure a stable embryonic nutrition and oxygen supply. This is a complex process which depends on many factors from both the embryo and the mother. We analyzed the methylation level of seven genes (ADORA2B, NPR3, PRDM1, PSG2, PHTLH, SV2C, and TICAM2) involved in placental development in the chorionic villi of spontaneous abortions with trisomy 16 (n = 14), compared with spontaneous abortions with a normal karyotype (n = 31) and the control group of induced abortions (n = 10). To obtain sequencing libraries, targeted amplification of individual gene regions using designed oligonucleot ide primers for bisulfite-converted DNA was used. The analysis was carried out using targeted bisulfite massive parallel sequencing. In the group of spontaneous abortions with trisomy 16, the level of methylation of the PRDM1 and PSG2 genes was significantly increased compared to induced abortions (p = 0.0004 and p = 0.0015, respectively). In the group of spontaneous abortions, there was no increase in the level of methylation of the PRDM1 and PSG2 genes, but the level of methylation of the ADORA2B gene was significantly increased compared to the induced abortions (p = 0.032). The results obtained indicate the potential mechanisms of the pathogenetic effect of trisomy 16 on the placental development with the participation of the studied genes.