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This review is devoted to a comprehensive analysis of DNA copy number variations (CNVs) identified in patients with neurodevelopmental disorders (NDDs) from the literature. The selection of publications was conducted using specifically developed criteria. CNVs were characterized based on their clinical significance, type of copy number alteration (microdeletion/microduplication), size, origin, and gene content. The study sample comprised 3375 patients with NDDs. Pathogenic and likely pathogenic CNVs, as well as variants of uncertain clinical significance, were identified in 395 individuals (12%). Chromosomal variations of each category were identified in 89 (3%), 56 (2%), and 241 (7%) patients, respectively. Nine individuals exhibited combinations of CNVs with different clinical significance. The number of duplications slightly exceeded the number of deletions (250 and 204, respectively). The size of most CNVs ranged from 193 bp to 400 kb and from 1 to 3 Mb (237 and 96, respectively). Seventy-two variants originated de novo, while 165 were inherited. Eighty-six CNVs were associated with 33 known microdeletion/microduplication syndromes. The most prevalent syndromes were 1q21.1 duplication (7/395, 1.8%) (OMIM: 612475), 2p16.3 deletion (9/395, 2.3%) (OMIM: 614332), 15q13.3 deletion (7/395, 1.8%) (OMIM: 612001), 16p11.2 deletion (9/395, 2.3%) (OMIM: 611913), and 22q11.2 duplication (7/395, 1.8%) (OMIM: 608363) syndromes. Enrichment analysis revealed that pathogenic CNVs, as well as variants of uncertain clinical significance, are enriched in genes associated with abnormal behavioral and neurological phenotypes. Likely pathogenic CNVs included genes associated with disorders of the nervous system and homeostasis/metabolism. [ABSTRACT FROM AUTHOR]

A brief history of the development of ideas about pleiotropy, its types, and the overall prevalence of pleiotropic loci in the human genome, as well as pleiotropic variants and genes within the same group of pathologies (disorders of psychomotor development) and between different diseases are discussed. Data on the association of the birth of a child with intellectual disability in a woman with a history of miscarriage are presented. The involvement of the same copy number variations (CNVs) in disorders of prenatal and postnatal development has been shown. The hypothesis is proposed that these CNVs are pleiotropic and manifested by one pathology or another, depending on additional modifying factors. [ABSTRACT FROM AUTHOR]

This review concerns the mechanisms of bacterial cell survival based on the induction of hibernation factors (HFs) that suppress protein synthesis via the inhibition of ribosomal functions. These factors include ribosome-binding proteins that inhibit 70S ribosomes (RaiA), form their inactive 100S dimers (RMF and HPF), or act at different stages of the translation cycle (RsfS, YqjD, SRA, and EttA). In some cells of the population, HFs cause the formation of a dormant state, which is characterized by a low rate of metabolic processes. This results in the tolerance of these cells and, as a consequence, the ability to persist in the presence of antibiotics and under stress conditions. The role of metabolic factors (polyamines and indoles) in the regulation of the expression levels of hibernation genes is discussed. [ABSTRACT FROM AUTHOR]

Bacterial persistence coupled with biofilm formation is directly associated with failure of antibiotic treatment of tuberculosis. We have now identified 4-(4,7-DiMethyl-1,2,3,4-tetrahydroNaphthalene-1-yl)Pentanoic acid (DMNP), a synthetic diterpene analogue, as a lead compound that was capable of suppressing persistence and eradicating biofilms in Mycobacterium smegmatis. By using two reciprocal experimental approaches – Δ rel Msm and Δ relZ gene knockout mutations versus rel Msm and relZ overexpression technique – we showed that both Rel Msm and RelZ (p)ppGpp synthetases are plausible candidates for serving as targets for DMNP. In vitro , DMNP inhibited (p)ppGpp-synthesizing activity of purified Rel Msm in a concentration-dependent manner. These findings, supplemented by molecular docking simulation, suggest that DMNP targets the structural sites shared by Rel Msm , RelZ, and presumably by a few others as yet unidentified (p)ppGpp producers, thereby inhibiting persister cell formation and eradicating biofilms. Therefore, DMNP may serve as a promising lead for development of antimycobacterial drugs. [Display omitted] • DMNP is a synthetic diterpene analogue inhibiting mycobacterial persistence • (p)ppGpp is an essential cell regulator of persistence and biofilm formation • DMNP targets Rel Msm , RelZ (p)ppGpp synthetases and inhibits their activities • Lack of (p)ppGpp reduces cell survival by limiting persistence and biofilm formation Tkachenko et al. revealed that DMNP, a synthetic analogue of natural marine diterpene erogorgiaene, binds to the structurally similar sites of Rel Msm , RelZ, and presumably of some other as yet unidentified (p)ppGpp producers thereby inhibiting persister cell formation and eradicating biofilms. [ABSTRACT FROM AUTHOR]

Skewed X-chromosome inactivation (sXCI) can be a marker of lethal genetic variants on the X chromosome in a woman since sXCI modifies the pathological phenotype. The aim of this study was to search for CNVs in women with miscarriages and sXCI. XCI was assayed using the classical method based on the amplification of highly polymorphic exon 1 of the androgen receptor (AR) gene. The XCI status was analysed in 313 women with pregnancy loss and in 87 spontaneously aborted embryos with 46,XX karyotype, as well as in control groups of 135 women without pregnancy loss and 64 embryos with 46,XX karyotype from induced abortions in women who terminated a normal pregnancy. The frequency of sXCI differed significantly between women with miscarriages and women without pregnancy losses (6.3% and 2.2%, respectively; p = 0.019). To exclude primary causes of sXCI, sequencing of the XIST and XACT genes was performed. The XIST and XACT gene sequencing revealed no known pathogenic variants that could lead to sXCI. Molecular karyotyping was performed using aCGH, followed by verification of X-linked CNVs by RT-PCR and MLPA. Microdeletions at Xp11.23 and Xq24 as well as gains of Xq28 were detected in women with sXCI and pregnancy loss. [ABSTRACT FROM AUTHOR]

Differentiation of induced pluripotent stem cells (iPSCs) from patients and healthy donors allows in vitro study of genetic disorders. The authors have previously reported a clinical case of recurrent pregnancy loss in a patient with skewed X-chromosome inactivation in peripheral blood lymphocytes, endometrium, and buccal epithelium. A 239 kb microdeletion at Xq24 that affected eight genes, including UBE2A, has been found. In this work, an iPSC line iTAF15Xsk4 was produced from the patient's skin fibroblasts using nonintegrating episomal vectors. The iPSC line had a normal karyotype, expressed pluripotency markers, and expressed markers of all three germ layers upon differentiation in embryoid bodies. This cell line could be used for the UBE2A deficiency syndrome study. [ABSTRACT FROM AUTHOR]

The presence of an extra chromosome in the embryo karyotype often dramatically affects the fate of pregnancy. Trisomy 16 is the most common aneuploidy in first-trimester miscarriages. The present study identified changes in DNA methylation in chorionic villi of miscarriages with trisomy 16. Ninety-seven differentially methylated sites in 91 genes were identified (false discovery rate (FDR) < 0.05 and Δβ > 0.15) using DNA methylation arrays. Most of the differentially methylated genes encoded secreted proteins, signaling peptides, and receptors with disulfide bonds. Subsequent analysis using targeted bisulfite massive parallel sequencing showed hypermethylation of the promoters of specific genes in miscarriages with trisomy 16 but not miscarriages with other aneuploidies. Some of the genes were responsible for the development of the placenta and embryo (GATA3-AS1, TRPV6, SCL13A4, and CALCB) and the formation of the mitotic spindle (ANKRD53). Hypermethylation of GATA3-AS1 was associated with reduced expression of GATA3 protein in chorionic villi of miscarriages with trisomy 16. Aberrant hypermethylation of genes may lead to a decrease in expression, impaired trophoblast differentiation and invasion, mitotic disorders, chromosomal mosaicism and karyotype self-correction via trisomy rescue mechanisms. [ABSTRACT FROM AUTHOR]