Uterine fibroids (UF) are the most common benign tumors of the reproductive system, yet their etiology and pathogenesis remain incompletely understood. Over the past 15 years, genome-wide association studies (GWAS) have become the primary tool for identifying genetic risk loci. The aim of this review is to evaluate the contribution of GWAS to the study of UF, to analyze the evolution of approaches, and to determine the relationship between the identified loci and the molecular mechanisms of the disease. Based on data from the GWAS Catalog, PubMed, and eLibrary, 13 GWAS studies and a number of replication studies were selected. GWAS have identified hundreds of loci involved in genome stability maintenance (TP53, TERT), urogenital system development (WNT4, MED12), hormonal regulation (GREB1), and other processes. Genetic overlap between UF and endometriosis as well as reproductive traits, along with ethnicity-specific effects, has been demonstrated. However, the number of replication studies remains limited. A transition from the analysis of individual loci to the integration of signals into pathophysiological pathways is emerging, underscoring the necessity of further confirmatory studies in independent populations.

Neurological disorders represent a broad group of human pathological conditions of varied severity, ranging from rare epileptic seizures and hearing loss to severe central nervous system pathologies. Numerous mutations in various genes linked to human neurological disorders have been described, and one of the examples are mutations in OXR1 and TBC1D24 genes, members of a highly conserved TLDc gene family. TLDc family members are found in eukaryotic genomes and are characterised by presence of conserved TLDc domain with unknown molecular function. It has been shown that TLDc family members play an important role in protection against oxidative stress, especially in the cells of the central nervous system, and regulate the function of vesicular ATPase, thus altering the intraluminal pH of vesicular organelles. Numerous mutations in the TBC1D24 gene have been identified in patients with various epilepsy types, hearing loss, as well as rare multisystem DOORS syndrome. During the last few years approximately ten patients with OXR1 mutations have also been described – their severe condition is characterised by microcephaly, neurodegeneration and profound developmental delay among other symptomes. This review briefly characterises TLDc protein family members’ functions and associated with their disturbance phenotypes of model organisms, and in details discusses the role of TLDc genes mutations in human diseases.

Introduction. This article presents the burden and diversity of hereditary pathologies (HP) among the ethnic Russian populace of the Republic of North Ossetia-Alania (RNOA). A comparative genogeographic analysis was conducted to identify patterns of HP variation across different regions and ethnic groups in European Russia.

Methods. The Russian populace of the RNOA was 108,206 individuals. The survey was conducted using the genetic-epidemiological research methodology developed for small populations at the Research Centre for Medical Genetics. The genetic burden (per 1,000 individuals examined) was calculated, and the diversity of HP for the ethnic Russian populace (AD, AR, X-linked) was described. Confirmatory DNA testing for most of the identified hereditary diseases was performed in the laboratories of the Center for Medical Genetics. The burden between settlements was compared using the χ² method, the prevalence of MNPs was compared using the Fisher test, and the analysis of genogeographic relationships between regions/ethnic groups was performed using cluster analysis.

Results. 78 nosological forms of HP were identified in the Russian populace of the RNOA. A total of 221 patients from 142 families with HP were registered. The cumulative prevalence of HP among the Russian populace in rural areas (1 case per 233 individuals) is three times higher than in the cities and district centers of the Republic of North Ossetia (1:659 people). A study of the spectrum of hereditary diseases among the Russian populace of the Republic of North Ossetia revealed patterns similar to those observed in other regions of Russia with a predominantly Russian populace, as well as in European populations. At this stage of the study, the similarity in the prevalence of individual diseases and the spectrum of identified genetic variants in the causal genes is most characteristic of the Russian ethnic group, despite the intensive interbreeding of the Russian populace (>20%).

Conclusions. A comparative gene-geographic analysis of the nosological spectrum and prevalence of hereditary diseases using clustering demonstrated the stability of the Russian gene pool, manifested in the preservation of both regionally specific patterns of hereditary diseases and their frequencies, as well as characteristic frequencies of major mutations in individual genes.

Introduction. Occupational exposure to a complex of genotoxic agents (coal dust, heavy metals, polycyclic aromatic hydrocarbons) at coal-fired thermal power plants (TPPs) can induce epigenetic changes, in particular, abnormal methylation of the promoters of key genome protection genes. However, the methylation status of DNA repair genes (XRCC1, XRCC2, XRCC3, ERCC2, ERCC5) and xenobiotic biotransformation genes (GSTP1, GSTT1, CYP1A1) in coal-fired TPP workers remains unstudied. Objective: To characterize the methylation profile of these promoters in coal-fired TPP workers compared with a control group and to evaluate the influence of occupational and individual factors.

Methods. A total of 936 individuals were examined: 445 workers at coal-fired power plants in Kemerovo and 491 residents not employed in industrial production. Promoter methylation status was determined using methylation-specific PCR after bisulfite conversion of DNA. Results were validated using whole-genome bisulfite sequencing (WGBS) on a subsample (n=5).

Results. A significant increase in the frequency of hypermethylated and partially methylated promoter status of all eight genes was revealed in thermal power plant workers compared to the controls (p <0.000001). The most pronounced differences were recorded for GSTP1, GSTT1 and ERCC5 (hypermethylation in workers was 4-5 times more frequent). Work experience of >20 years was associated with a higher frequency of hypermethylation of ERCC2, XRCC1, XRCC3 (p <0.02). Workers in the fuel and transport, repair, chemical shops and the thermal automation and measurements shop demonstrated the highest rates of hypermethylation of ERCC2, ERCC5 and GSTT1 (p < 0.02). No significant associations of methylation status with gender, age, smoking and the presence of chronic diseases were found (p > 0.05).

Conclusion. The obtained data demonstrate for the first time a significant shift in the epigenetic profile toward hypermethylation of repair and detoxification gene promoters during work at coal-fired power plants. Work experience and occupational location are key determinants of epigenetic changes. The obtained results substantiate the use of these markers for biomonitoring of occupational risks.

Background. Papillary renal cancer (PRC) is the second most common malignant renal neoplasm. Rare hereditary forms of PRC are presented by several monogenic diseases with partially overlapping phenotypes. Therefore, improving the effectiveness of molecular genetic diagnostics and medical genetic counseling for hereditary PRC is an actual problem.

Methods. We have analyzed 32 genomic DNA samples from patients with hereditary papillary renal cell carcinoma (HPRC) and hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndromes using sequencing and multiplex ligase-dependent probe amplification.

Results and discussion. Point pathogenic/likely pathogenic variants were identified in 5 families. The c.3274G>A (MET) and c.395_399del (FH) variants previously not described as common mutations, although we have detected those variants in two or more probands from different families in our cohort. Duplication of exons 5-21 of the MET gene was detected in 21% of HPRC cases. This duplication is currently of uncertain clinical significance, but in silico predictors indicate its pathogenicity. Also, we propose management of mutation carriers and an improved diagnostic protocol for hereditary PRC in accordance with international consensus.

Conclusions. Diagnosis of hereditary PRC requires analysis of both point mutations and copy number of the MET and FH genes considering the tumor type.

Mitochondrial DNA depletion syndrome-6 is a group of rare autosomal recessive disorder characterized by the early onset and severe manifestation, high risk death within the first year of life. This case report describes the clinical manifestations of MPV17-related hepatocerebral mtDNA depletion syndrome. The most laboratory findings revealed raised serum lactate and hypofibrinogenemia. The initial symptoms of the disease were nonspecific: reduced appetite, regurgitation, and a flat weight curve. Patients with rapidly progressive liver damage require indepth molecular genetic testing to verify hereditary diseases, determine therapeutic strategies, and assess prognosis for the child. It is very important to confirm the disease for family consulting.

The aim of the present study was to investigate the association of functionally significant single nucleotide polymorphisms (SNPs) in genes encoding key enzymes of glutathione biosynthesis with the pattern of coronary artery involvement in patients with coronary artery disease as assessed by coronary angiography. The SNP rs11165048 in the GCLM gene was found to be associated with a decreased risk of left main coronary artery stenosis. The rs6933870 polymorphism in GCLC was associated with an increased risk of circumflex artery stenosis. The rs16883912 variant of GCLC was associated with a reduced risk of right coronary artery (RCA) stenosis, whereas the rs7752556 (GCLC) and rs7517826 (GCLM) polymorphisms were associated with an increased risk of RCA stenosis. Furthermore, the rs7752556, rs6933870, and rs13212365 variants of GCLC were associated with the risk of left anterior descending artery stenosis. This study provides the first evidence that polymorphisms in glutathione biosynthesis genes, particularly GCLC and GCLM, are associated with atherosclerotic lesions in distinct coronary artery branches in patients with coronary artery disease.