Background. Danon disease is a rare X-linked lysosomal storage disorder with multisystem involvement in man and with predominant heart affection in female patients. Cardiomyopathy is the most severe and life-limiting manifestation for both sexes, often requiring heart transplantation (HT) in early adulthood. It is recognized as one of the genetic causes of the hypertrophic cardiomyopathy (HCM) phenotype. Objective. To assess the prevalence and clinical characteristics of Danon disease adult patients with primary HCM phenotype who underwent HT. Patients and methods. 11 adult patients (8 female) with HCM diagnosis and HT history were enlisted. Targeted next-generation sequencing of 39 or 108-gene panels related to cardiomyopathies was performed. Carriers of pathogenic or likely pathogenic variants   in the LAMP2 gene were analyzed in detail. Results. In 3 out of 11 patients (27%, all were female) causing LAMP2 variants were identified: (1) start-loss variant c.T2C:p.Met1Thr, (2) intronic variant resulting in splicing alterations c.G865-1A, (3) nonsense-variant c.G962A: p.Trp321Ter. There were no signs of liver, muscular and nervous systems involvement, one patient had retinitis pigmentosa. The cardiac phenotype evolved from HCM to a dilated phase, with severe biventricular systolic dysfunction, atrial fibrillation, thromboembolic complications and high-grade ventricular arrhythmias (including ventricular fibrillation in one patient). Heart failure onset occurred at 26-29 years; HT was performed at 28–32 years. All three patients had chronic lymphocytic myocarditis diagnosed on myocardium histology. Conclusion. Genetic testing for the diagnosis of Danon disease should be considered in women with heart failure onset in young adulthood and hypertrophy, restriction and/or dilatation as the cardiomyopathy phenotype hallmarks. Myocarditis may contribute to progression of fibrosis and heart failure in these patients, but the role of immunosuppressive therapy remains to be clarified.

Background. The investigation of genetic causes underlying the dilated phenotype of cardiomyopathy (CMP) in children is of particular interest. In Russia, publications on pediatric dilated phenotype CMP are limited to isolated case reports; longitudinal studies of large cohorts integrating clinical presentation with genetic data are lacking. Aim: to describe the clinical and molecular genetic characteristics of Russian pediatric patients with dilated cardiomyopathy and analyze   correlations between disease course and identified genetic variants. Methods. Medical records of 250 children with myocardial remodeling demonstrating a dilated phenotype were analyzed. Genetic testing was performed using high-throughput sequencing for all patients, with subsequent validation of results via bidirectional Sanger sequencing. Genetic findings were correlated with patients’ clinical characteristics. Results. A genetic etiology of dilated phenotype CMP was identified in 196 patients. Over 75% of cases were attributed to sarcomeric gene variants, with mutations in thin filament genes associated with the most severe disease course. The study established clinical and genetic characteristics of CMP and identified laboratory and instrumental predictors of adverse disease outcomes. Conclusion. Early molecular genetic diagnosis in children with CMP not only enables optimized patient management, initiation of family screening, and disease outcome prediction but also lays the foundation for future development of targeted therapies.

Hypertrophic cardiomyopathy (HCM) is a common hereditary disease. Clinical polymorphism regarding age of onset and disease progression, which is evident even in the carriers of the same pathogenic variant, suggests the influence of additional factors, including genetic ones, on the HCM phenotype. In this study, a search was conducted for an association between the TPM1 and TNNT2 gene polymorphisms and echocardiographic parameters variability in patients with HCM. An association of the left ventricular ejection fraction value with genotypes for two variants (rs1071646 and rs111470259 located in the non-coding regions of the TPM1 gene) was found. These variants may be important for the regulation of gene expression. An association with the interventricular septum thickness, left ventricular mass, and left ventricular mass index was also found for rs1071646. The obtained results allow us to assume that in addition to pathogenic variants in the genes of sarcomeric proteins, which are necessary for the development of the disease, some individual polymorphisms can have a modifying effect on the formation of the HCM phenotype.

Hypertrophic cardiomyopathy (HCM) is the most common hereditary myocardial disease, which occurs with a frequency of 1:500-1:200 of the adult population in all ethnic groups. In the pediatric population, the HCM prevalence is about 1 in 47,000. The disease is characterized by pronounced genetic heterogeneity, however, most cases of HCM are caused by rare variants in the MYH7 and MyBPC3 genes, with more than 90% of mutations in the MyBPC3 gene representing shortening variants leading to the formation of a premature stop codon. In most patients with a single shortening variant in the MyBPC3 gene, clinical manifestations develop over the age of 35, and cases of manifestation in childhood are quite rare. Therefore, the detection of atypically early cases of manifestation always raises questions about the genetic and non-genetic factors influencing the development of the disease. We present a description of a clinical case of MyBPC3-associated HCM in a child characterized by rapid disease progression, development of left ventricular outflow tract obstruction, and the need for cardiac surgery at the age of 12 years. The report presents the results of dynamic follow-up of the patient for eight years before and after surgical treatment. The features of the course of the disease caused by the pathogenic variant of the MyBPC3 gene and the factors influencing the prognosis of the disease are discussed.

Introduction. The c.1073C>T (p.Ser358Leu, rs63750743) variant in the TMEM43 gene causes a rare form of arrhythmogenic cardiomyopathy type 5 (ACM5), characterized by significant fatty infiltration of the myocardium, electrical conduction abnormalities, and a high risk of sudden cardiac death (SCD) – often the first manifestation of the disease. Objective: to present the clinical case of a female patient with the p.Ser358Leu variant, initially diagnosed with idiopathic ventricular tachycardia (IVT), later reclassified as biventricular arrhythmogenic cardiomyopathy (ACM); and to describe the spectrum of phenotypic manifestations of p.Ser358Leu in other carriers. Methods. A 65-year-old female patient experienced recurrent sustained ventricular tachycardia (VT). Clinical work-up included 12-lead ECG, transthoracic echocardiogram (TTE), cardiac magnetic resonance imaging (MRI) with late gadolinium enhancement (LGE), 24-hour ECG monitoring, and coronary angiography. Genetic analysis was performed using next-generation sequencing (NGS) of a panel of 174 genes linked to inherited cardiovascular diseases. There was a family history of three male relatives who died suddenly. Results. ECG showed sinus bradycardia, reduced R-wave amplitude in V1–V3, and T-wave inversions in leads III and aVF. Holter ECG revealed isolated and paired ventricular extrasystoles, single supraventricular extrasystoles, and an episode of idioventricular rhythm. Cardiac MRI demonstrated morpho-functional abnormalities consistent with the biventricular form of ACM per the 2020 Padua criteria. Due to hemodynamically significant VT, a cardioverter-defibrillator (ICD) was implanted. The was detected in the TMEM43 gene. The pathogenic variant c.1073C>T (p.Ser358Leu, rs63750743) in TMEM43 gene was detected. Conclusion. The pathogenic p.Ser358Leu variant in TMEM43 exhibits variable phenotypic expression but is most often considered a malignant nucleotide substitution, associated with early-onset ACM and high SCD risk, especially in males. This case confirms the very high risk of SCD in p.Ser358Leu carriers and highlights the difficulty of detecting myocardial structural changes in such individuals. Therefore, screening for the p.Ser358Leu TMEM43 mutation should be included not only in patients with ACM, but also in individuals with IVT when no pathogenic variants are found in channelopathy-associated genes.

Background. Hypertrophic cardiomyopathy (HCM) is one of the most common forms of cardiomyopathy in children, characterized by a variable age of onset and variyng severity of clinical manifestations. In most cases, the causative variants of HCM are unique substitutions and are located in the genes encoding the proteins of the thick and thin myofilaments of the sarcomere. In Russia, publications on the characteristics of HCM are limited to the preschool age, small cohorts, and are primarily focused on syndromic forms of HCM, such as hereditary metabolic diseases and RASopathies. Aim: to describe the clinical and molecular genetic characteristics of Russian pediatric patients with hypertrophic cardiomyopathy. Methods. The case histories of 206 children with HCM were analyzed. Molecular genetic testing was performed by high-throughput sequencing, with subsequent validation of the results by bidirectional Sanger sequencing. All patients underwent determination of NTproBNP levels and an instrumental examination that included echocardiography, electrocardiography, and daily Holter monitoring, in some cases, cardiac MRI with intravenous contrast was also performed. Results. In 71% of patients, the cause of the disease was identified as nucleotide variants in the genes encoding the thick and thin filaments of the sarcomere, with a predominance of variants in the MYH7 gene (54%). Pathogenic variants in sarcomere-associated and other genes of monogenic HCM were found in 9% of patients, while in 11% of cases, no definitive genetic cause for myocardial hypertrophy could be identified. The obstructive form of the disease was diagnosed in 66 (32%) patients, half of which were caused by nucleotide variants in the MYH7 gene (p < 0.001). In contrast, the highest intraventricular obstruction gradient (>50 mm Hg) was identified in patients with variants in the TPM1, MYL3, and CACNA1C genes (p < 0.025). This study defines the clinical and genetic characteristics of a cohort with HCM (n=206), from which cases of hereditary metabolic diseases and RASopathies were excluded. Conclusion. Genetic verification of HCM is of fundamental importance for understanding the pathogenesis in each clinical case, determining treatment strategy, assessing disease prognosis, and enabling the development and implementation of targeted therapy. The study demonstrates differences in disease progression depending on the causative gene, most clearly manifested in patients with MYH7-HCM and MYBPC3-HCM, as well as the necessity of genetic testing for children with myocardial hypertrophy born to mothers with gestational diabetes. Given the relatively high percentage of “negative” results of the genetic test, the presence of causative variants in non-coding genomic regions, as well as a multifactorial disease etiology, can’t be ruled out. This necessitates continued research into the genetic background of HCM in various regions of the country.

Connective tissue disorders (CTD) is a group of common hereditary diseases that occur in aa population of at least 1:2000 of the population, including at least 200 nosological forms. The most serious CTD complication is aneurysms of the aorta and its branches, which reduces patients’ life expectancy. Аneurysms usually do not cause complaints and remain unrecognized for a long time. This publication presents a family case of Loyes-Dietz syndrome with an unusual combination of genetic and environmental risk factors for aortic rupture in several relatives, which led to an accumulation of sudden deaths in two generations and the need for high-risk surgery in the third one. The article discusses the tactics of medical and genetic counseling for families with Loyes-Dietz syndrome, the importance of timely DNA diagnostics, surgical methods of treatment, and prevention of life-threatening complications.

The contradictory findings regarding the comorbidity of thoracic aortic aneurysm and atherosclerosis underscore the need to identify shared and distinct molecular genetic factors underlying the relationship between these pathologies. Particular interest lies in investigating epigenetic modifications, specifically DNA methylation, in patients with concurrent thoracic aortic aneurysm and atherosclerosis. This study aimed to identify differentially methylated genes involved in both isolated and atherosclerosis-comorbid aortic pathology across aortic tissue, blood, and skin samples from patients with non-syndromic forms of thoracic aortic aneurysm. Differential methylation patterns of the non-coding RNA gene NR2F1-AS1 were identified between isolated and comorbid forms of aortic aneurysm and atherosclerosis: hypomethylation was observed in the dilated aortic region and atherosclerotic plaques of thoracic aortic aneurysm patients, whereas hypermethylation was detected in atherosclerotic plaques from patients with atherosclerosis without aneurysm. The results demonstrate bidirectional alterations in methylation levels within the non-coding RNA gene NR2F1-AS1 in both thoracic aortic aneurysm and aortic atherosclerosis, highlighting the significant role of non-coding RNAs in the pathogenesis of these conditions.

Hypertriglyceridemia (HTG) is a disorder of lipid metabolism characterized by an increase in the level of triglycerides (TG) in blood plasma of more than 1,7 mmol/l. The level of TG ≥10 mmol/l, according to some literature data, or ≥ 11.2 mmol/l, according to others, is considered a severe form of HTG. A number of factors are responsible for the development of this pathology: pathogenic or likely pathogenic variants in the gene or genes associated with HTG, the presence of metabolic diseases, environmental factors, and lifestyle. The most dangerous phenotypic manifestation of elevated TG levels in blood plasma is the development of acute pancreatitis, for which patients often seek medical help for the first time. In this study, we describe two clinical cases of severe HTG that we observed, in which the diagnostic search consisted of molecular genetics and instrumental methods. As a result of the study of the biological material of patients by sequencing, the following were identified: in the first case, a heterozygous, probably pathogenic variant in the LPL gene and a probably benign variant in the LMF1 gene; in the second, a heterozygous variant of unclear clinical significance in the LMF1 gene. The article discusses the possible causal role of these genetic variants and the complexity of the clinical interpretation of heterozygous causes of HTG.

Introduction. Extreme hypertriglyceridemia (HTG) often has a hereditary nature. Besides the classic lipolysis genes (LPL, APOC2, APOA5), the significance of the transcription factor gene CREB3L3 remains understudied in the Russian population. Aim: to assess the contribution and characterize the clinical and laboratory features of CREB3L3-associated hypertriglyceridemia. Methods. A clinical and molecular examination of 103 patients with extreme HTG (triglyceride level >10 mmol/L) was conducted. Sequencing of the “Hereditary Hyperlipidemias” gene panel and whole-exome sequencing were used. For phenotypic assessment, the lipid profile and the diagnostic scale by Moulin et al. (2018) were applied. Results. A monogenic origin of HTG was confirmed in 24 patients (23.3%). The CREB3L3-associated form was identified in 9 individuals, accounting for 37.5% of all hereditary cases. Its phenotype differed from classical familial hyperchylomicronemia by a significantly higher HDL level (0.95 vs. 0.47 mmol/L, p<0.05) and a lower score on the Moulin scale (8 vs. 12, p<0.001). A recurring variant, c.733_738delinsGAAAAAT (p.Lys245GlufsTer130), was found in 66.7% of patients with CREB3L3-HTG, which is not registered in Russian population databases. Conclusion. CREB3L3 is the second most significant gene in the structure of monogenic hypertriglyceridemias in the Russian Federation. Its associated form has a distinctive laboratory profile, which is important for differential diagnosis. The identification of a frequent variant suggests the possibility of targeted screening. The inclusion of CREB3L3 in diagnostic panels for patients with extreme HTG is clinically justified.

Duchenne muscular dystrophy (DMD) is a severe, recessive X-linked disease caused by pathogenic variants in the DMD gene. Nonsense and frameshift variants typically result in a more severe phenotype, DMD, whereas non-frameshift mutations produce a truncated but partially functional dystrophin, leading to a milder phenotype known as Becker muscular dystrophy. The primary therapeutic strategy for DMD involves frameshift correction to achieve a Becker-like phenotype. This study aimed to disrupt splice sites in exons 11 and 12 of the DMD gene to restore the reading frame using CRISPR-Cas gene editing. Six guide RNAs (gRNAs) for SpCas9 and SaCas9 nucleases were selected. In the initial screening phase conducted in HEK293T cells, three gRNAs targeting exon 11 and one targeting exon 12 were identified as the most effective. Experiments in myoblasts derived from a DMD patient with deletions of exons 12–18 revealed that the efficiency of exon 11 skipping was low, likely due to the introduction of extensive deletions near the canonical splicing site. Conversely, the skipping efficiency of exon 12 in immortalized myoblasts from a healthy donor averaged 9.2% of alleles. Further research is needed to optimize exon 12 skipping in patient-specific cells to confirm successful restoration of dystrophin protein production.

Uterine fibroids (UF) are characterized by excessive deposition of extracellular matrix (ECM) proteins such as collagens, fibronectin and proteoglycans, leading to fibrosis and aberrant tissue remodeling, which is crucial for UF. The aim of our study was to analyze the associations of polymorphic variants of the MMP1, MMP2, MMP3, MMP9 genes with the risk of UF. A protective effect of the SNP rs243865 (C/T) MMP2 relative to UF was found, and exclusively in the group of patients without a history of pelvic inflammatory disease (protective allele T: OR = 0.63, 95% CI = 0.43-0.91, p = 0.01). Functional annotation revealed that rs243865 may be involved in the molecular mechanisms of the disease through the regulation of apoptosis, cell proliferation, sex hormone levels, and cell signaling.

The structure of diseases is heterogeneous, which is manifested by various combinations of diseases, including comorbidities, as well as diseases that rarely manifest together. The aspects of genetic susceptibility to a co-occurrence of bronchial asthma (BA) with atopic dermatitis (AD), allergic rhinitis (AR), and hypertension (HD) were studied. The associations of polymorphic variants of candidate genes with the development of tuberculosis (TB), a disease rarely manifesting together in patients with allergic BA, were assessed. The features of the pathogenetics of the co-occurrence (syntropy) of BA with AD, AR, and HD, as well as the rare co-occurrence (dystropy) of BA with TB, were established.

The current tactics of managing a 33-year-old woman, a carrier of a frequent pathogenic variant of the BRCA1 gene, are presented. The role of medical genetic counseling for women with inherited breast and ovarian cancer syndrome is mapped. Data on the importance of the use of genetic testing in clinical practice for predicting the development of cancer, conducting personalized dynamic observation, informing about options for reducing the risk of surgical interventions, possible treatment, conducting preimplantation research as the primary prevention of hereditary oncological syndromes are presented.

This article presents a description of a clinical case of a patient with Krabbe disease. This diagnosis was confirmed by determining the level of enzymatic activity of galactocerebrosidase and molecular genetic testing – searching for mutations in the GALC gene.

Connective tissue dysplasias (CTD) are a genetically heterogeneous group of inherited diseases characterised by abnormalities in the structure and functions of the connective tissue. In the study group of children with CTD, a molecular genetic study using high-throughput sequencing (HTS) technology was performed. Pathogenic variants in the genes: FGFR3, COL3A1, PLOD2, FKBP14, EBP, ANO5 and SLC26A2 were identified in 14 patients. These mutations correlate with different clinical phenotypes ranging from classic Marfan syndrome to rare forms. The results highlight the genetic heterogeneity of CTD and the importance of a high-throughput sequencing for a personalised approach in the diagnosis and the prognosis of the disease.

There is described the experience of long-term enzyme replacement therapy of adult patients with various lysosomal storage diseases-mucopolysaccharidosis Is, mucopolysaccharidosis type IVA, Fabry disease and the specifics of their management in the region.

Hermansky-Pudlak Syndrome (HPS) is a rare (1-9 per 1 million people) hereditary disorder characterized by oculocutaneous albinism, impaired platelet aggregation, and potential systemic complications such as pulmonary fibrosis, granulomatous colitis, and cardiomyopathy. To date, 11 types of HPS have been described, associated with mutations in various genes encoding components of the AP3 and BLOC protein complexes, which play a key role in the formation of intracellular organelles. As part of a scientific and diagnostic program for the study of albinism conducted at the Research Centre for Medical Genetics (RCMG) since 2018, one of the largest Russian cohorts of patients with Hermansky-Pudlak syndrome has been established. The study included 21 patients from 15 families, who underwent comprehensive clinical and instrumental examinations, molecular genetic testing, and medical genetic counseling. Ophthalmologic examinations revealed that all patients had macular hypoplasia of at least grade 2, which explains the significant reduction in visual acuity, as well as hypermetropia of varying severity. Progressive cataracts with childhood-onset were diagnosed in 19% of cases. An important ophthalmologic distinction between HPS and oculocutaneous albinism type 1A was the retention of   partial pigmentation in the iris and retinal pigment epithelium, which correlated with a moderate degree of iris transillumination. The characteristic appearance of the optic nerve head (grayish-pink coloration in 86% of cases) may lead to diagnostic errors and misinterpretation of lesions as optic nerve atrophy. Analysis of clinical data showed that 100% of HPS patients had a history of hemorrhagic conditions, which was confirmed by abnormalities in coagulation tests. All patients with HPS1 and HPS4 reported abdominal pain, highlighting the need to include gastroenterological examination in the diagnostic protocol. Molecular genetic analysis, performed using high-throughput sequencing (targeted panels, whole-exome, and whole-genome sequencing) followed by Sanger sequencing verification, identified causative genes. Mutations in the HPS1 gene were the most frequently detected (48% of cases). These findings emphasize highlight the need for further research of Hermansky-Pudlak syndrome using a comprehensive approach to diagnosis, including extended molecular genetic testing and multidisciplinary examination.

In Russia in 2022 45900 children aged 0-14 years have congenital malformations (CM), accounting for 3.6% of all live births [1]. Next generation sequencing plays a crucial role in identifying the genetic etiology of CM. In the absence of genetic findings in children with CM, additional clinical symptoms may emerge during careful dynamic observation, enabling reanalysis of exome data. This increases the likelihood of identifying new genotype-phenotype correlations.

Objective: To investigate the population-specific features of immune response gene polymorphisms, including IFNG (rs2069727), IL1B (rs1143634), IL6 (rs1800796), IL10 (rs1800896), CX3CR1 (rs3732379), and CTLA4 (rs3087243), which are associated with the development of idiopathic recurrent pregnancy loss (iRPL) in an ethnically homogeneous Kazakh population. Additionally, to conduct a comparative analysis with previously studied global populations. Methods: Genomic database analysis was performed using genotyping data from 1,900 conditionally healthy Kazakh individuals, covering approximately 2.5 million SNPs. The data were obtained using OmniChip 2.5M Illumina arrays at the DECODE Genomics Center in Iceland as part of the collaborative “Genetic Studies of Preeclampsia in Central Asian and European Populations” (InterPregGen) project, funded by the 7th Framework Program of the European Commission (Grant Agreement No. 282540). Results: The study reveals significant inter-population diversity in the minor allele frequencies (MAFs) of the analyzed SNPs. East Asian populations exhibit the most distinct differences compared to European and Kazakh populations, likely due to genetic isolation and historical migration processes. Conclusion: The genome-wide analysis has guided the selection of pro- and anti-inflammatory immune system gene polymorphisms for further replication genotyping in Kazakh women with iRPL. The obtained results will serve as a foundation for developing effective early diagnostic methods for idiopathic recurrent pregnancy loss.

The gene pool of the Tyumen Siberian Tatars (n=124) was studied according to the STR markers of the Y chromosome. Genotyping of DNA samples revealed the presence of four main haplogroups in the gene pool of the Tyumen Tatars - R-Z93, O–M134, N-F4205 and N-Z1936, which indicates the contribution of different migration flows (Volga-Ural region, Siberia, East Asia) in the formation of the gene pool of the Tyumen Tatars. On the one hand, these are influences from Asia, and on the other, Siberia and the Volga-Ural region.

This article presents data on the molecular basis of the comorbidity of Gaucher disease, a rare hereditary disorder, with Parkinson’s disease, a common neurodegenerative condition. It is discussed that this association may be broader and extend to other genes of lysosomal storage diseases. Approaches to the treatment of Parkinson’s disease are discussed, that are uncovered as a result of our own data obtained in recent years.

Parkinson’s disease (PD) is a common neurodegenerative disorder with a long latent period, necessitating the search for genes and mechanisms involved in its pathogenesis at the earliest stages (ES). The aim of this study was to investigate changes in gene expression at the transcriptome level in PD and to identify novel biomarkers of early-stage disease. A whole-transcriptome analysis of peripheral blood from monozygotic twins discordant for PD was performed, followed by real-time PCR validation of the results. In the blood of twins with PD, altered expression of three genes associated with circadian rhythms – PTGDS, ADORA2A, and MTA1 – was demonstrated. Expression analysis of individual candidate genes was also conducted in the peripheral blood of early-stage PD patients. This analysis revealed a significant and PD-specific alteration in the expression of MTA1, HNMT, NSF, PTGS2, and LRRN3 genes in early-stage PD patients. These genes may be involved in the pathogenesis of PD and may also be considered as potential biomarkers for early-stage PD.

Pathogenic variants in the SMN1 gene are the underlying cause of autosomal recessive spinal muscular atrophy (SMA), a condition that is included in the list of expanded neonatal screening. SMA is diagnosed primarily by qPCR, a method that is subject to several limitations. The objective of this study was to develop an approach that would enhance the accuracy of SMA diagnosis by employing digital PCR. To this end, a novel technique was developed that facilitates the concurrent evaluation of exon 7 deletion in the SMN1 gene and the simultaneous calculation of the SMN1, SMN2, and RPP30 gene dosages, employing a mere two fluorescent channels as a reference. The study utilized anonymized DNA samples of newborns obtained from dried blood spots, in accordance with standard protocols employed for expanded neonatal screening. The study’s findings yielded the development of specific primers, a digital PCR design, and a method for analyzing the results, including a comparative analysis with the generally recognized “gold standard” MLPA. The developed method enables the accurate evaluation of exon 7 deletion in the SMN1 gene, as well as the dosage of the SMN1 and SMN2 genes, within a single digital PCR reaction. This advancement has the potential to serve as a diagnostic tool for SMA, particularly in cases that are subject to controversy during neonatal screening.

In megalopolis, dynamics of the gene pool is mediated by unequal natural increase of ethnic groups and variable migration processes. Prognosis of dynamics of the gene pool of megalopolis under action of genetic demographic processes is actual for ensuring demographic and genetic security of population. Using data of demographic statistics and questionnaire data of residents, parameters of migration and spectrum of ethnic groups in the migration flows to megalopolis were studied. In three generations of Moscow residents, haplogroups of Y-chromosome were predicted by means of Internet-predictor Whit Athley’s by 18 STR of Y-chromosome. Taking into account intensity of migration flows and ethnoterritorial composition of migrants arriving in the megalopolis, long-term prognosis was performed for dynamics of haplogroups of Y-chromosome. Technique applied for compilation of the genetic prognosis is universal, and might be used for any genetic markers, including markers of hereditary diseases.

Introduction. Currently, the issue of chemo-induced resistance and restoration of homologous recombination gene activity in the treatment of patients with breast cancer (BC) remains open. Aim: to study the relationship between homologous recombination deficiency (HRD) and the effectiveness of treatment and to assess the compensability of the BRCA-like phenotype under the influence of chemotherapy drugs. Methods. The study included 130 patients with BC. For in vitro studies, the following breast cancer cell lines were used: MCF-7, MDA-MB-231, MDA-MB-468. The analysis of HRD parameters was performed using: microarray analysis, RT-PCR and NGS. Results. Hyperexpression of CHEK1, PARP1, BRCA1 is associated with tumor progression, as well as the appearance of amplifications in the BRCA1, BARD1, CHEK1 genes and others (83% of cases). Work on in vitro models made it possible to establish that under the influence of chemotherapy drugs, the state of the homologous recombination system is restored, and this may be one of the reasons for the formation of tumor cell resistance. Conclusions. The presence of HRD in a breast tumor is an important marker in a personalized approach to treatment. However, the question of overcoming the formation of tumor resistance due to HRD compensatory remains open, which undoubtedly requires further study.

Patients with mild cognitive impairment (MCI) are at high risk of disease progression to Alzheimer’s disease (AD). Identifying genetic risk factors, such as the ε4 allele of the APOE gene, biomarkers corresponding to the early stages of AD, and assessing polygenic risk (PRS) with the potential for further stratification of patients into risk groups, may aid in predicting disease progression and prevention. The aim of this study is to develop a molecular method for analyzing genetic markers to assess the impact of polygenic risk values on the development of dementia and the dynamics of cognitive functions in patients with varying degrees of cognitive decline. A biochip was developed for the analysis of 21 risk markers and the ε2/ε3/ε4 alleles of the APOE gene. PRS values corresponding to the fourth quartile, as well as the presence of APOE-ε4, showed a significant association with an increased risk of developing dementia. PRS positively correlated with tTau and pTau181 and negatively correlated with the Aβ42/Aβ40 ratio. APOE-ε4 carriers had higher levels of tTau and pTau181 and lower levels of Aβ42 and Aβ42/ Aβ40. Concentrations of IP-10, FGF-2, and VEGF were significantly associated with the APOE genotype. Patients with the APOE ε4/ε4 genotype exhibited lower baseline cognitive scores and negative cognitive dynamics. The lack of a significant association between PRS and cognitive function dynamics may be due to timely provision of appropriate medical care for the prevention of cognitive impairments.