The application of array-based comparative genomic hybridization and next-generation sequencing has identified many chromosomal microdeletions and microduplications in patients with different pathological phenotypes. Different copy number variations are described within the short arm of chromosome 18 in patients with skin diseases. In particular, full or partial monosomy 18p has also been associated with keratosis pilaris. Here, for the first time, we report a young male patient with intellectual disability, diabetes mellitus (type I), and keratosis pilaris, who exhibited a de novo 45-kb microduplication of exons 4-22 of LAMA1, located at 18p11.31, and a 432-kb 18p11.32 microduplication of paternal origin containing the genes METTL4, NDC80, and CBX3P2 and exons 1-15 of the SMCHD1 gene. The microduplication of LAMA1 was identified in skin fibroblasts but not in lymphocytes, whereas the larger microduplication was present in both tissues. We propose LAMA1 as a novel candidate gene for keratosis pilaris. Although inherited from a healthy father, the 18p11.32 microduplication, which included relevant genes, could also contribute to phenotype manifestation.

Enzymes CYP4A11 and CYP4F2 are involved in biosynthesis of vasoactive 20-hydroxyeicosatetraenoic acid and may contribute to pathogenesis of coronary artery disease (CAD). We investigated whether polymorphisms of the CYP4A11 and CYP4F2 genes are associated with the risk of CAD in Russian population. DNA samples from 1323 unrelated subjects (637 angiographically confirmed CAD patients and 686 age- and sex-matched healthy individuals) were genotyped for polymorphisms rs3890011, rs9332978, and rs9333029 of CYP4A11 and rs3093098 and rs1558139 of CYP4F2 by using the Mass-ARRAY 4 system. SNPs rs3890011 and rs9332978 of CYP4A11 were associated with increased risk of CAD in women: OR = 1.26, 95% CI: 1.02-1.57, P = 0.004, and Q = 0.01 and OR = 1.45, 95% CI: 1.13-1.87, P = 0.004, and Q = 0.01, respectively. Haplotype G-C-A of CYP4A11 was associated with increased risk of CAD (adjusted OR = 1.41, 95% CI: 1.12-1.78, and P = 0.0036). Epistatic interactions were found between rs9332978 of CYP4A11 and rs1558139 of CYP4F2 (Pinteraction = 0.025). In silico analysis allowed identifying that SNP rs9332978 is located at a binding site for multiple transcription factors; many of them are known to regulate the pathways involved in the pathogenesis of CAD. This is the first study in Europeans that reported association between polymorphism rs9332978 of CYP4A11 and susceptibility to coronary artery disease.

Copy number variations (CNVs) of the human CNTN6 gene caused by megabase-scale microdeletions or microduplications in the 3p26.3 region are often the cause of neurodevelopmental disorders, including intellectual disability and developmental delay. Surprisingly, patients with different copy numbers of this gene display notable overlapping of neuropsychiatric symptoms. The complexity of the study of human neuropathologies is associated with the inaccessibility of brain material. This problem can be overcome through the use of reprogramming technologies that permit the generation of induced pluripotent stem (iPS) cells from fibroblasts and their subsequent in vitro differentiation into neurons. We obtained a set of iPS cell lines derived from a patient carrier of the CNTN6 gene duplication and from two healthy donors. All iPS cell lines displayed the characteristics of pluripotent cells. Some iPS cell lines derived from the patient and from healthy donors were differentiated in vitro by exogenous expression of the Ngn2 transcription factor or by spontaneous neural differentiation of iPS cells through the neural rosette stage. The obtained neurons showed the characteristics of mature neurons as judged by the presence of neuronal markers and by their electrophysiological characteristics. Analysis of allele-specific expression of the CNTN6 gene in these neuronal cells by droplet digital PCR demonstrated that the level of expression of the duplicated allele was significantly reduced compared to that of the wild-type allele. Importantly, according to the sequencing data, both copies of the CNTN6 gene, which were approximately 1 Mb in size, showed no any additional structural rearrangements.

Cognitive performance is an important endophenotype for various neurodegenerative and neuropsychiatric traits. In the present study two genetic variants in the leucine-zipper protein (LUZP2) and the F-box 40 protein (FBXO40) genes, previously reported to be genome-wide significant for Alzheimer's diseases and schizophrenia, were examined for an association with cognitive abilities in normal elderly fromthe Russian population. Rs1021261 in the LUZP2 and rs3772130 in the FBXO40 were genotyped bymultiplex PCR and MALDI-TOF mass spectrometry in a sample of 708 normal elderly subjects tested for cognitive performance using the Montreal Cognitive Assessment (MoCA). Association of genetic variability with theMoCA scores was estimated by parametric and nonparametric analysis of variance and by the frequency comparison between upper and lower quartiles of MoCA distribution. Significantly higher frequency of ""TT"" genotype of rs1021261 in the LUZP2 gene aswell as ""A"" allele and ""AA"" genotype of rs3772130 in the FBXO40 gene was found in a subsample of individuals with the MoCA score less than 20 comparing to the fourth quartile's subsample (MoCA > 25). The data of the present study suggests that genetic variability in the LUZP2 and FBXO40 loci associated with neurodegenerative and neuropsychiatric diseases is also contributed to the normal variability in cognitive performance in the elderly.

Каждый сотый новорожденный имеет порок сердца, и в 10% случаев они являются причиной младенческой смертности. Генетические изменения могут стать основой возникновения сердечно-сосудистых аномалий. У части пациентов с врожденными пороками сердца, сопровождающимися экстракардиальной патологией, могут быть выявлены патогенные вариации числа копий ДНК. В настоящем исследовании 15 пациентам в возрасте от 1 месяца до 4 лет, перенесшим оперативное лечение по поводу врожденного порока сердца, был проведен полногеномный анализ с использованием ДНК-микрочипов высокого разрешения SurePrint G3 Human Genome CGH Microarray Kit, 8х60K. Все пациенты имели экстракардиальную патологию. У 7 из 15 (46%) детей выявлены патогенные и вероятно патогенные вариации числа копий ДНК: у 4 пациентов диагностирован синдром микроделеции 22q11.2, по одному пациенту имели синдромы микроделеции 7q11.23 и микроделеции 1p36, еще один пациент имел микродупликацию в регионе 20p13. Полученные данные свидетельствуют о том, что aCGH отличается высокой диагностической ценностью при выявлении геномного дисбаланса у детей с врожденными пороками сердца и экстракардиальной патологией.

Вариации числа копий ДНК (CNVs) являются одной из генетических причин врожденных пороков сердца (ВПС). Существующие представления о CNVs в этиологии ВПС не могут полностью объяснить формирование того или иного порока сердца, поэтому актуально более глубокое изучение этого явления. Полученные знания будут направлены на разработку новых подходов для улучшения диагностики геномного дисбаланса у пациентов с ВПС. Цель. Изучить представленность патогенетически значимых CNVs в нозологической структуре ВПС и обнаружить связь между патогенетически значимыми CNVs и аномальным строением сердца. Материалы и методы. 31 ребенок с ВПС, сочетающимся с экстракардиальной патологией был включен в исследование. Образцы ДНК были проанализированы с использованием ДНК-микрочипов высокой плотности SurePrint G3 Human Genome CGH+SNP Microarray Kit, 8х60K (Agilent Technologies, США). Для описания нозологической структуры использовали МКБ-11. Результаты. У 32% (10/31) пациентов с ВПС и экстракардиальной патологией были выявлены патогенетически значимые CNVs. CNVs были представлены в следующих категориях ВПС: аномалии желудочков и их перегородки; аномалии межпредсердной перегородки; аномалии вентрикуло-артериального клапана или смежных областей; аномалии вен средостения. 8 из 10 пациентов с патогенными и потенциально патогенными CNVs имели септальные дефекты или конотрункальные пороки сердца, у 9 из 10 - порок сердца включал более одной аномалии. Выводы. У пациентов c конотрункальными, септальными или сложными ВПС и экстракардиальной патологией с большей вероятностью возможно обнаружение клинически значимых CNVs.

A comparative analysis of gene expression profiles of carotid atherosclerotic plaques and intact internal thoracic arteries of patients with advanced atherosclerosis was performed by using the Human-12 BeadChip Microarray (Illumina, USA). The most down-regulated genes in the carotid atherosclerotic plaques were APOD, FABP4, CIDEC, and FOSB, in contrast, up-regulated gene was SPP1 ( > 64; pFDR < 0.05). The majority of differentially expressed genes were down-regulated in advanced atherosclerotic plaques. For example, genes involved in immune and inflammatory responses (arachidonic acid metabolism, cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, Jak-STAT signaling pathway, TNF signaling pathway) were down-regulated in advanced atherosclerotic plaques as compared with the healthy arteries. The most significant biological process of genes down-regulated in carotid atherosclerotic plaques (compared to intact internal thoracic arteries) was “cellular response to metal ions” (metallothioneins), and for upregulated genes was the organization of the extracellular matrix.

Background: Ring chromosome instability may influence a patient's phenotype and challenge its interpretation.

Results: Here, we report a 4-year-old girl with a compound phenotype. Cytogenetic analysis revealed her karyotype to be 46,XX,r(22). aCGH identified a 180 kb 22q13.32 duplication, a de novo 2.024 Mb subtelomeric 22q13.32-q13.33 deletion, which is associated with Phelan-McDermid syndrome, and a maternal single gene 382-kb TUSC7 deletion of uncertain clinical significance located in the region of the 3q13.31 deletion syndrome. All chromosomal aberrations were confirmed by real-time PCR in lymphocytes and detected in skin fibroblasts. The deletions were also found in the buccal epithelium. According to FISH analysis, 8% and 24% of the patient's lymphocytes and skin fibroblasts, respectively, had monosomy 22.

Conclusions: We believe that a combination of 22q13.32-q13.33 deletion and monosomy 22 in a portion of cells can better define the clinical phenotype of the patient. Importantly, the in vivo presence of monosomic cells indicates ring chromosome instability, which may favor karyotype correction that is significant for the development of chromosomal therapy protocols.

A developed method of multiplex genotyping of polymorphic markers of genes associated with cognitive abilities and neuropsychiatric diseases is based on multilocus PCR and MALDI-TOF mass spectrometry of DNA molecules. The frequencies of 32 single-nucleotide markers localized in 24 genes are analyzed in a sample of elderly people from the Russian population of Tomsk. The data obtained are compared with data for populations from the 1000 Genomes Project.

Specificity of the structure of gene pools of different ethno-territorial groups of the human population can underlie the epidemiological features of the spread of tuberculosis (TB) and the structure of the genetic component of the susceptibility to the disease. The variability of 62 genetic variants potentially associated with the risk of the development of TB in the Russian population of the city of Tomsk has been studied and the differentiation of various ethno-territorial groups of the world by these markers has been assessed. The studied sample comprised 445 Russian residents of the city of Tomsk without bronchopulmonary pathology. For comparison, the data on the variability of the genetic markers of interest in 26 populations from the 1000 Genomes Project was involved. In the Tomsk population, only the ancestral allele was found for seven of the 58 SNPs studied; the allele frequencies for 36 markers were within the limits of the values seen in other European populations; for 12 SNPs, the observed frequencies were closer to populations with a significant Mongoloid component. By the total of the SNPs, the Tomsk population, despite the geographical distance from the rest of the European populations, did not differ from them (in genetic distances and Gst statistics), although it had some features of the gene pool. Intergroup differentiation of the world populations by these SNPs reflects mainly interracial differences. The greatest differences in the genetic structure between the studied populations were seen for the markers localized in intergenic regions. Statistically significant differences were found when comparing the levels of the average expected heterozygosity between groups of “L4 carrier populations” of mycobacteria and “non-L4” populations, which indicates the impact of the prevalence of different pathogenic lineages of M. tuberculosis on the formation of population specificity of the allelic frequencies.

To study associations between genes of different functional classes, including fibrogenesis genes, with coronary atherosclerosis and specific features of its course. Methods. We included in this study404 patients with confirmed chronic ischemic heart disease (IHD) who had undergone coronary artery bypass grafting. Two groups of participants were distinguished - those with (n=188) and without (n=216) history of myocardial infarction (MI). Control group consisted of inhabitants of the Siberia region (n=285). Associations were analyzed using 48 single nucleotide polymorphisms (SNP) located in genes earlier determined as associated with diseases of the cardiovascular continuum (diabetes mellitus, MI, atherosclerosis). Multiplex genotyping was performed using mass spectrometry. For statistical analyses we used Statistica v8.0 and R-language with “stats” and “genetics” packages. Results. We identified several genetic markers contributing to susceptibility to development of atherosclerosis. Same markers were identified as determinants of the character ofthe course of atherosclerotic disease. Risk of development of atherosclerosis was higher in carriers of the following genotypes: TT of ITGB5 gene (rs1007856) - by 1.6 times (OR=1.59; р=0.0153); GG of ITGA4 gene - by 1.85 times (OR=1.85; р=0.0016); GG of IGFBP7 gene (rs11133482) - by 2.4 times (OR=2.36; р=0.0031). The following genotypes were identified as protective against MI and determining stable course of the disease: AA of TLR4 gene (rs4986790) (OR=0.47; р=0.0104).; CC of LDLR gene (rs2738446) (OR=0,53; р=0.0041); GG of OAS1 gene (rs1131454) (OR=0.50; р=0.0274). Conclusion. Susceptibility to coronary atherosclerosis and prognosis of disease progression were found to be associated with polymorphism of certain genes, involved in metabolism of the extracellular matrix and processes of fibrogenesis (ADAMDEC1, ITGA4, ITGB5, CDKN2B-AS1, IGFBP7), lipid metabolism (LDLR), immune system functioning (TLR4, OAS1) and DNA repair (LIG1).

This article contains data on the frequencies of alleles, genotypes and haplotypes of the single nucleotide polymorphisms (SNPs) rs2279590 and rs1532278 in the CLU gene in a cohort of normal elderly from the Russian population. The SNPs have been reported to be associated with Alzheimer's disease and cognitive functions in genome-wide and candidate genes association studies. Cognitive performance in sample set was estimated by the Montreal Cognitive Assessment (MoCA). The frequencies of alleles, genotypes and haplotypes of two SNPs were calculated in 3 groups: total sample set, sample set with MoCA score less than 21 (the first quartile) and group with MoCA score more than 24 (the fourth quartile).

The prevalence of comorbid diseases poses a major health issue for millions of people worldwide and an enormous socio-economic burden for society. The molecular mechanisms for the development of comorbidities need to be investigated. For this purpose, a workflow system was developed to aggregate data on biomedical entities from heterogeneous data sources. The process of integrating and merging all data sources of the workflow system was implemented as a semi-automatic pipeline that provides the import, fusion, and analysis of the highly connected biomedical data in a Neo4j database GenCoNet. As a starting point, data on the common comorbid diseases essential hypertension and bronchial asthma was integrated. GenCoNet (https://genconet.kalis-amts.de) is a curated database that provides a better understanding of hereditary bases of comorbidities.

Skin fibroblasts from a patient with intellectual disability and ring chromosome 22 were reprogrammed into induced pluripotent stem cells (iPSCs) to establish a clonal stem cell lines, IMGTi001-A (iTAF5-29) and IMGTi001-B (iTAF5-32). Because of ring chromosome mitotic instability these cell lines show mosaic karyotypes with 46,XX,r(22) in >83% cells, 45,XX,-22 as minor class and sporadically cells with other karyotypes. Differentiation in derivatives of all three germ layers was shown in teratoma assay for IMGTi001-A, and in embryoid bodies for both cell lines. To our knowledge, human iPSC lines with ring chromosome are described for the first time.

The review focuses on the functional role of histamine and the genetic factors involved in maintaining the physiological level of this amine in the organism, as well as on the involvement of histamine and genes of the histamine pathway in the development of several common diseases. Histamine is a biogenic amine with a wide range of competencies, the physiological effects of which are realized with the help of four types of receptors (HRH1, HRH2, HRH3, and HRH4), characterized by tissue-specific expression. The key genes responsible for maintaining the physiological level of histamine are HDC (responsible for the synthesis of endogenous histamine), AOC1, HNMT, MAOB, and ALDH7A1 (involved in the degradation of histamine and its metabolites). However, in total, according to Gene Ontology, proteins and enzymes encoded by more than 200 genes are involved in the histamine pathway. Both temporal and chronic imbalances between the synthesis/intake of histamine and its degradation/metabolism in the human body (including those caused by specific genetic features) mediate the development of inflammatory manifestations with disturbance of the homeostasis of various organ systems (nervous, immune, endocrine, cardiovascular, etc.). Immunopathologic reactions mediated by histamine accompany the development of antigen-specific and nonspecific immediate and delayed-type hypersensitivity reactions of inflammation, effector immunocomplex reactions, autoimmune disorders, and cancer and, ultimately, can determine the comorbidity of common diseases. The review also provides information on the associations of the genes of the histamine pathway with common diseases (according to the studies using the candidate-gene approach and genome-wide association studies).