Molecular Genetic Aspects Research Articles

Circumscribed choroidal hemangioma in Sturge-Weber syndrome

We report on a19-year-old patient with Sturge-Weber syndrome (SWS), accompanied by aNaevus flammeus, secondary glaucoma, and glaucomatous optic atrophy of the right eye. The painful and blind eye was enucleated. Histopathological analysis revealed acircumscribed choroidal hemangioma around the optic nerve and asmaller extrascleral hemangioma. Molecular genetic testing excluded GNA11, GNAQ, or GNAS mutations. Our work illuminates the clinical, histological, and molecular genetic aspects of this rare case, contributing to the differential diagnosis of ocular conditions in patients with SWS.

Chronicles of A.I. Pospelov Moscow Society of Dermatovenerologists and Cosmetologists (MSDС was founded on October 4, 1891) Bulletin of the MSDС № 1157

On April 16th we held our last meeting of A.I. Pospelov Moscow Society of Dermatologists and Cosmetologists in person. There were 102 participants and 5 applicants. Our agenda included two clinical cases: the first one was a clinical case of fulminant acne (Miderm Clinic); the second one was about gangrenous pyoderma as a possible marker or paraneoplasia in intestinal oncological diseases (Sechenov University). We present clinical cases of patients with fulminant acne and periorbital oedema in the first report, and ascending colon tumour and T3N0M0 rectal cancer in the second report. Three reports were presented in the scientific part of the meeting: the effectiveness of therapy for severe psoriasis (Sechenov University), the effectiveness of Janus kinase inhibitors in atopic dermatitis (Sechenov University), the molecular genetic aspects of the fungal mycosis pathogenesis (State Scientific Center of Dermatovenerology and Cosmetology). The authors presented the results of their own clinical studies of the effectiveness of therapy of diseases, including in the report on molecular-genetic aspects of the pathogenesis of mycosis fungoides the author assessed the changes in the expression levels of genes of the JAK-STAT signalling pathway and transcription factors both in visually unaffected skin and in the focus of clinically detectable lesions.

Intragenic dystrophin (DMD) duplication variant in Entlebucher Mountain Dogs with Duchenne muscular dystrophy.

Muscular dystrophies represent a group of disorders characterized by progressive muscle degeneration and weakness. An important subgroup are the dystrophin-related muscular dystrophies caused by variants in the DMD gene. They can be divided into the more severe Duchenne muscular dystrophy and the milder Becker muscular dystrophy. Here, we characterize the clinical, histopathological and molecular genetic aspects of two male Entlebucher Mountain Dogs with clinical signs of muscular dystrophy. The two dogs presented with marked dysphagia starting at the age of several weeks and in the later course recognizable exercise intolerance with highly increased serum creatine kinase levels. Histopathological signs of a dystrophic myopathy represented by degeneration of muscle fibers and signs of regeneration were present. Whole genome sequencing of one affected dog identified an intragenic 8.6 kb duplication in the X-chromosomal DMD gene, c.7528-4048_7645 + 4450dup. No other protein-changing variants in candidate genes for muscular dystrophy were identified. The duplication includes exon 52 of DMD and is predicted to lead to a frameshift and truncation of 30% of the wild-type open reading frame. Genotyping of the whole family confirmed the presence of the mutant allele in both affected dogs and the unaffected dam. The correct co-segregation of the mutant allele in the affected family as well as knowledge from humans and other species suggest the identified DMD variant as the most likely candidate variant for the muscular dystrophy phenotype in the two investigated dogs.

Molecular genetics of Dupuytren's contracture.

Dupuytren's contracture (DC) is a fibroproliferative disorder of the palmar fascia characterised by the digits' flexion contractures and is associated with abnormal build-up of type III collagen. The prevalence of the disease is reported to be highest among Northern European descendants. However, the disease is widespread globally with varying prevalence. DC is a multifactorial disease, having both genetic and environmental factors contributing to the causality of the disease. Over the years, various studies have been conducted to understand the molecular mechanism and genetic aspects of DC but there is a lack of reports on the variants found in the exonic regions. Most reports are backdated making it necessary to re-evaluate the variants to further understand the genetic aetiology of DC. In this review, we first highlight the genetic aspects and previous genetic studies on DC. The report is followed by a discussion on the molecular pathways suggested to be associated with DC and a summary of the genetic variants in the exonic regions found in DC and their connections with the molecular pathways. A total of nine variants were reported originating from six genes comprising three pathways. Most variants reported are involved in the Wnt signalling pathway. Moreover, all variants identified are in European/Caucasian subjects and the variants found in the exonic regions are missense variants. A comparison of these findings with variants from populations of other regions can be conducted to identify the variants with the most occurrence to act as biomarkers or therapeutic targets for DC.

Mycobacterium Tuberculosis Resistance — Stages of Drug Resistance Formation (Review)

The review contains an analysis of the latest research on molecular genetic aspects of the formation of resistance in tuberculosis patients to avoid it during use of modern treatment programs. Objective — to assess the situation with the evolution of resistance of Mycobacteria tuberculosis and the stages of drug resistance development using materials from available databases. Materials and methods. The research has been completed for the period from 2014 to 2024. The next stage with the establishment of a systemic topological and metric computer analysis of the results allowed us to see the most informative sections of the research topic that are clearly associated with the formation mechanisms of drug-resistance in pulmonary tuberculosis. The most complete database of available literary sources was obtained (about 50 out of 502 analyzed arrays). Results and discussion. Ukraine is among the thirty countries with a high burden of tuberculosis with multiple drug resistance (MDR-TB). The main threat to the effectiveness of tuberculosis treatment in Ukraine is late detection of the disease and determining the sensitivity of the pathogen, which is the main prerequisite for prescribing adequate treatment. The situation with MDR-TB in Ukraine remains difficult in the conditions of war against the background of the COVID-19 pandemic. Thus, the total number of such cases for 2023 was 1,955 patients, of which 1,326 were new cases. The number of cases of tuberculosis with extended resistance (XDR-TB) was 228, of which 136 patients were diagnosed for the first time. Conclusions. The question of studying the genetic aspects of the formation of drug resistance of M. tuberculosis with the determination of the role of polymorphic variants of genes encoding xenobiotic metabolism systems in tuberculosis infection remains relevant to understand the mechanisms of interaction in the process of implementing hereditary information at the holistic level of the organism in order to increase the effectiveness of treatment and prevent the formation of resistance.

Molecular Genetic Aspects of Sporadic Multiglandular Primary Hyperparathyroidism.

Multiglandular primary hyperparathyroidism (MGD) represents a rare form of primary hyperparathyroidism (PHPT). MGD is associated with hereditary PHPT, but the sporadic MGD is more common and affects a similar patient profile as single gland parathyroid disease (SGD). The distinction between SGD and MGD is of great clinical importance, especially for the strategy of parathyroidectomy. Based on the limited knowledge available, MGD is likely to be a genetically heterogeneous disease resulting from the interaction of germline and somatic DNA mutations together with epigenetic alterations. Furthermore, these events may combine and occur independently in parathyroid tumors within the same individual with MGD. Gene expression profiling has shown that SGD and MGD may represent distinct entities in parathyroid tumorigenesis. We are waiting for studies to analyze exactly which genes are different in SGD and MGD in order to identify potential biomarkers that can distinguish between the two forms of the disease.

Molecular-genetic portrait of virulence of Stenotrophomonas maltophilia

Introduction. Stenotrophomonas maltophilia is an opportunistic pathogen that is intrinsically resistant to a wide range of antibiotics. The bacterium is associated with a number of serious diseases and makes a significant contribution to the pathogenesis of polymicrobial infections. S. maltophilia has a wide range of virulence factors, information about which is currently presented in the form of scattered and unconsolidated data.
 Purposes and objectives: critically analyze and summarize current data regarding the molecular-genetic aspects of S. maltophilia virulence for better understanding of the pathogenesis of infections associated with this pathogen.
 Materials and methods. An analysis of information from 80 modern literary sources devoted to the study of the virulent properties of S. maltophilia at the molecular-genetic level has been carried out. The analysis focuses on the mechanisms of production of virulence factors and their genetic determinants.
 Results.The molecular mechanisms of virulence that determine the infectious process caused by S. maltophilia have been analyzed and summarized, including the adhesive function of the surface structures of the bacterial cell (lipopolysaccharides, pili/fimbriae, flagella), the production of extracellular enzymes, the ability to form biofilms on abiotic surfaces and on the tissues of the macroorganism, the functioning of efflux pumps, secretion of small molecules into the external environment by the intercellular information exchange system Quorum Sensing, as well as the influence of iron metabolism on the virulence properties of S. maltophilia.
 Conclusion. The adaptation mechanisms that allow S. maltophilia to adapt to new habitat niches and survive in the human body and unfavorable environmental conditions have been poorly studied. An analytical review summarizing current information on the molecular-genetic aspects of S. maltophilia virulence will be of interest to clinicians and researchers studying the fundamental mechanisms of virulence.

Молекулярно-генетические аспекты развития атопического дерматита

Молекулярно-генетические аспекты развития атопического дерматита

Polyphenols in Plants: Structure, Biosynthesis, Abiotic Stress Regulation, and Practical Applications (Review).

Phenolic compounds or polyphenols are among the most common compounds of secondary metabolism in plants. Their biosynthesis is characteristic of all plant cells and is carried out with the participation of the shikimate and acetate-malonate pathways. In this case, polyphenols of various structures are formed, such as phenylpropanoids, flavonoids, and various oligomeric and polymeric compounds of phenolic nature. Their number already exceeds 10,000. The diversity of phenolics affects their biological activity and functional role. Most of their representatives are characterized by interaction with reactive oxygen species, which manifests itself not only in plants but also in the human body, where they enter through food chains. Having a high biological activity, phenolic compounds are successfully used as medicines and nutritional supplements for the health of the population. The accumulation and biosynthesis of polyphenols in plants depend on many factors, including physiological-biochemical, molecular-genetic, and environmental factors. In the review, we present the latest literature data on the structure of various classes of phenolic compounds, their antioxidant activity, and their biosynthesis, including their molecular genetic aspects (genes and transfactors). Since plants grow with significant environmental changes on the planet, their response to the action of abiotic factors (light, UV radiation, temperature, and heavy metals) at the level of accumulation and composition of these secondary metabolites, as well as their metabolic regulation, is considered. Information is given about plant polyphenols as important and necessary components of functional nutrition and pharmaceutically valuable substances for the health of the population. Proposals on promising areas of research and development in the field of plant polyphenols are presented.

The molecular genetic aspects of basal cell carcinoma from the position of population health preservation

The exploration of molecular genetic mechanisms that underlie carcinogenesis, hereditary factors of various oncological diseases, including basal cell carcinoma, the most common type of skin cancer is especially actual and significant for target strategies of public health. The diagnosis of basal cell carcinoma is based on complex clinical, radiologic and genetic examination data. The further research in the field of somatic or hereditary mutations in genes associated with basal cell carcinoma, including Patched 1 (PTCH1), Patched 2 (PTCH2), Smoothed (SMO) continue to be topical. The strategies of primary prevention of basal cell carcinoma, discussions of complex issues of decision-making concerning treatment at primary health care level, training courses and development of guidelines for general practitioners and interdisciplinary recommendations for effective early diagnosis and comprehensive care of basal cell carcinoma are to be suggested.

Stem cell properties of cancer cells in ascitic fluid of patients with ovarian cancer: a key to control over cancer progression

Ovarian cancer is considered to be the most malignant and aggressive tumor of the female reproductive system, which is largely associated with early development of malignant ascites and peritoneal carcinomatosis. Cancer cells representing the primary focus, as well as those contained in the ascitic fluid, are extremely heterogeneous in terms of morphological, immunohistochemical, and molecular genetic aspects. Cancer stem cells play a significant role in tumor self-renewal, differentiation, metastasis, and development of chemoresistance.This literature review is aimed at summarizing the available data on cancer stem cells in ovarian cancer and their role in tumor progression. A bioinformatic search was carried out in the PubMed, NCBI, Google Scholar, and eLibrary databases using the keywords “cancer stem cells”, “ovarian cancer”, “malignant ascites”, “chemoresistance”, etc.The data presented in the review make it possible to comprehensively characterize the role of stem cell properties of ovarian cancer cells. The review presents up-to-date information on the molecular and biological parameters of cancer stem cells in ovarian cancer, which are the cellular component of malignant ascites, as well as data from the authors’ studies. Along with this, the article describes modern ideas about the mechanisms of formation of cellular spheroids and their contribution to cancer progression.Cancer stem cells are an extremely promising target in the development of future therapeutic strategies based on the study of signaling pathways in ovarian cancer stem cells, the mechanisms of spheroid formation, and the contribution of immune cells to the acquisition of cancer stem cell properties.

Exosomal non coding RNAs as a novel target for diabetes mellitus and its complications.

Diabetes mellitus (DM) is a first-line priority among the problems facing medical science and public health in almost all countries of the world. The main problem of DM is the high incidence of damage to the cardiovascular system, which in turn leads to diseases such as myocardial infarction, stroke, gangrene of the lower extremities, blindness and chronic renal failure. As a result, the study of the molecular genetic mechanisms of the pathogenesis of DM is of critical importance for the development of new diagnostic and therapeutic strategies. Molecular genetic aspects of the etiology and pathogenesis of diabetes mellitus are intensively studied in well-known laboratories around the world. One of the strategies in this direction is to study the role of exosomes in the pathogenesis of DM. Exosomes are microscopic extracellular vesicles with a diameter of 30-100nm, released into the intercellular space by cells of various tissues and organs. The content of exosomes depends on the cell type and includes mRNA, non-coding RNAs, DNA, and so on. Non-coding RNAs, a group of RNAs with limited transcriptional activity, have been discovered to play a significant role in regulating gene expression through epigenetic and posttranscriptional modulation, such as silencing of messenger RNA. One of the problems of usage exosomes in DM is the identification of the cellular origin of exosomes and the standardization of protocols for molecular genetic studies in clinical laboratories. In addition, the question of the target orientation of exosomes and their targeted activity requires additional study. Solving these and other problems will make it possible to use exosomes for the diagnosis and delivery of drugs directly to target cells in DM. This study presents an analysis of literature data on the role of exosomes and ncRNAs in the development and progression of DM, as well as the prospects for the use of exosomes in clinical practice in this disease.

Editorial introductions.

Current Opinion in Cardiology was launched in 1985. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of cardiology is divided into 14 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Editor and Section Editors for this issue. SECTION EDITORS Ali J MarianAli J MarianDr Marian received his training in clinical cardiology and human molecular genetics at Baylor College of Medicine, Houston, USA. He was appointed as a faculty at the Section of Cardiology at Baylor College of Medicine, Houston, USA in 1992. He joined the Institute of Molecular Medicine in 2006 to lead the Center for Cardiovascular Genetics. Dr Marian is recognized for his research achievements in molecular genetics and clinical aspects of cardiomyopathies. He has published over 200 articles in peer-reviewed journals, which collectively have garnered over 12,000 citations and an H index of 60. He received the Young Investigator Award from the American College of Cardiology, the Established Investigator Award from the American Heart Association, the Clinician-Scientist Award in Translational Research from Burroughs Wellcome Fund, Distinguished Scientist Award from Baylor St Luke's Medical Center, and the Best Editor Award from the American Heart Association Circulation Research. Dr Marian is currently a Deputy Editor for Cardiovascular Research, Section Editor on Genetics for Current Opinion in Cardiology, and the Editor-in-Chief of The Journal of Cardiovascular Aging. He is a former Deputy Editor for Circulation Research, Associate Editor for Circulation and European Journal of Clinical Investigation. Dr Marian's research is supported by R01 grants from the NHLBI-NIH, Leducq Foundation Trans-Atlantic Network of Excellence, and local foundations. Gene KimGene KimDr Kim is a cardiologist with the Advanced heart failure, Cardiac transplant, and Mechanical Circulatory Support Program at the University of Chicago Medicine, USA. He is an Associate Professor of Medicine and the Advanced Heart Failure Fellowship Program Director. His medical school, residency, and fellowship training were completed at the University of Chicago, USA. Dr Kim also directs the Genetic Cardiomyopathy and Hypertrophic Cardiomyopathy Clinics at University of Chicago, USA. Dr Kim's research interests include the genetic and epigenetic regulation of heart failure and arrhythmogenesis with publications on the role of microRNAs in cardiomyopathy. His interests also include myocardial recovery, extracellular matrix in failing myocardium. He has published over 100 articles and book chapters and is an investigator in numerous clinical trials. Bhavadharini RamuBhavadharini RamuDr Bhavadharini (Dharini) Ramu is an Advanced Heart Failure & Transplant Cardiologist, Director of the Cardio-Obstetrics Program and an Associate Professor of Medicine at the University of Minnesota, USA. She completed her internal medicine residency and cardiology fellowship at the University of Connecticut, USA followed by Advanced Heart Failure Fellowship at the University of Minnesota, USA in 2016. She previously served on the faculty at the Medical University of South Carolina, USA from 2016 to 2023. Dr Ramu has been an invited faculty lecturer at scientific meetings of the American College of Cardiology (ACC), Heart Failure Society of America, American Society of Transplantation, and International Society of Heart & Lung Transplantation. She is a member of the ACC's Heart Failure & Transplant Section Leadership Council, the program planning committee for the ACC's Scientific Sessions, and serves on the leadership council of the Women in Heart Transplantation & MCS Network. Dr Ramu's research interests include increasing the understanding of and reducing the impact of health-related disparities in patients with advanced heart failure, with a goal of reducing health inequities and improving the health of disadvantaged and vulnerable populations. She has served as a peer reviewer for many journals and is an investigator in heart failure clinical trials.

АССОЦИАЦИИ ПОЛИМОРФНОГО ВАРИАНТА RS3823082 ГЕНА ВАЗОИНТЕСТИНАЛЬНОГО ПЕПТИДА У ПАЦИЕНТОВ С РАЗЛИЧНЫМИ ФЕНОТИПАМИ БРОНХИАЛЬНОЙ АСТМЫ

Bronchial asthma (BA) is a complex, heterogeneous and one of the most common respiratory diseases affecting both children and adults worldwide. The identification of new genetic loci and the elucidation of the molecular mechanisms in which these loci are involved and affect the risk of developing AD will help complement the pathogenesis of AD. Since VIP affects the tone of the airways, it can be assumed that it affects the course of bronchial asthma, and the study of molecular genetic aspects can provide new diagnostic markers for the course of bronchial asthma. Target. Search for an association of frequencies of genotypes and alleles of the rs3823082 polymorphic variant of the vasointestinal peptide gene in patients with different phenotypes of bronchial asthma. 104 patients with moderate and severe BA were examined. Genotyping of the rs3823082 polymorphic loci was performed by real-time polymerase chain reaction. We found that the CC genotype of the VIP rs3823082 gene is associated with the development of the BA phenotype with a late onset (p=0.019; OR=4.0). The C allele is also a risk marker for the development of the BA phenotype with a late onset (p=0.002; OR=3.09). The CC genotype of the VIP rs3823082 gene is protective against the development of the BA phenotype with obesity (p=0.024; OR=0.167). The results obtained underline the importance of finding genetic variants of VIP, which allow predicting the development of a particular phenotype of bronchial asthma.

Molecular and genetic aspects of the pathogenesis of COVID-associated thrombosis

Annotation. COVID-19 is a viral infectious disease that reached pandemic proportions in 2020. The SARS-CoV-2 virus, which is the etiological factor of the coronavirus disease, has a complex mechanism of impact on the human body, causing various manifestations and causing complications of the disease. As you know, a severe form of coronavirus infection is associated with dire consequences, among which the main step is a violation of the coagulation system, which has the appearance of CVD syndrome, but its main symptom is thrombosis of arterial and venous vessels. The frequency of occurrence of thrombocytopenia forces us to investigate the pathogenesis of the development of this process to reduce the number of cases. However, there is still no clear opinion about the pathogenesis of such thrombosis. Therefore, the purpose of this review was to analyse the most probable mechanisms of development of venous and/or arterial thrombosis associated with coronavirus disease. In the course of the study, 64 information sources were analysed, extracted from PubMed, Web of Science, Google Scholar, and Elsevier databases. At the beginning of a thorough analysis of information, the following main links of COVID-associated thrombosis were identified: direct hyperactivation of blood platelets, which leads, through the participation of their surface molecules (P-selectin, CD40L, etc.), to the activation of aggregation and adhesion of platelets; ACE2 - mediated cell activation and endothelial dysfunction, which together have the property of stimulating thrombus formation; activation of the NETosis process, the MAPK pathway, Toll-like receptors and the Nox2 enzyme system, which also through a cascade of various reactions, which are described below, cause thrombosis. We understood that these several pathogenetic chains can work relatively separately, but the difficulty in describing the development of thrombotic disease caused by the SARS-CoV-2 virus is that these aspects of pathogenesis are closely related and intertwined at different links, forming both direct and feedback loops, and vicious circles. The obtained structured data can serve as a basis for further original research, which will allow the development of targeted therapy for the treatment and prevention of post-covid thromboses, directed at the described molecular genetic aspects.

Dystrophin (DMD) Missense Variant in Cats with Becker-Type Muscular Dystrophy

Muscular dystrophy due to dystrophin deficiency in humans is phenotypically divided into a severe Duchenne and milder Becker type. Dystrophin deficiency has also been described in a few animal species, and few DMD gene variants have been identified in animals. Here, we characterize the clinical, histopathological, and molecular genetic aspects of a family of Maine Coon crossbred cats with clinically mild and slowly progressive muscular dystrophy. Two young adult male littermate cats exhibited abnormal gait and muscular hypertrophy with macroglossia. Serum creatine kinase activities were highly increased. Histopathologically, dystrophic skeletal muscle exhibited marked structural changes including atrophic, hypertrophic, and necrotic muscle fibers. Immunohistochemistry showed irregularly reduced expression of dystrophin but the staining of other muscle proteins such as β- and γ-sarcoglycans as well as desmin was also diminished. Whole genome sequencing of one affected cat and genotyping of the littermate found both to be hemizygous mutant at a single DMD missense variant (c.4186C>T). No other protein-changing variants in candidate genes for muscular dystrophy were detected. In addition, one clinically healthy male littermate was hemizygous wildtype, while the queen and one female littermate were clinically healthy, but heterozygous. The predicted amino acid exchange (p.His1396Tyr) resides in a conserved central rod spectrin domain of dystrophin. Various protein modeling programs did not predict major disruption of the dystrophin protein by this substitution, but the altered charge of the region may still affect protein function. This study represents the first genotype-to-phenotype correlation of Becker-type dystrophin deficiency in companion animals.

Molecular features of malignant gastric tumors

Gastric cancer is one of the most widespread cancers and makes a significant contribution to the global mortality rate from malignant neoplasms. The late onset of clinical symptoms is the main reason why the disease is often diagnosed at an advanced stage, and this limits the available therapeutic approaches. Despite the fact, that extensive studies have been carried out to identify the mechanisms and markers of the development and progression of the disease, their results are currently not fully included in clinical practice. As a consequence, only marginal improvement in long-term survival has been achieved and patient prognosis remains poor. Understanding the molecular genetic features of gastric malignant tumors can provide insight into their pathogenesis, help identify new biomarkers for prognosis and diagnosis, and identify new therapeutic targets. In recent decades, advances in high throughput sequencing technologies have improved understanding of the molecular genetic aspects of gastric cancer. This review considers molecular level changes, including information on tumor suppressor genes, oncogenes, cell cycle and apoptosis regulators, cell adhesion molecules, loss of heterozygosity, micro-satellite instability and epigenetic aberrations (change in methylation level and modification of histones). The review is also devoted to the molecular aspects of pathogenesis – changes in the signaling pathways involved in the gastric cancer development; the classification of sporadic and hereditary gastric cancer at the molecular genetic level is considered. The characteristics and classification of GC presented in this review at the genetic and epigenetic levels confirms that this disease is heterogeneous. These data can be used both to develop and test potential markers and new targeted therapeutic approaches.

К вопросу об этиологии, диагностике и лечении кератоконуса

Purpose. To improve the methods of diagnosis and treatment of keratoconus (КС) based on the study of clinical and functional, molecular genetic and epidemiological characteristics of this disease in the Republic of Bashkortostan (RB). Material and methods. 477 patients with КС (954 eyes), 115 close relatives of КC patients were examined. The analysis of epidemiological indicators of КC in the RB was carried out based on the materials of the annual reports of the ophthalmological service for a 7-year period. The study of molecular genetic aspects of КC was carried out in 181 patients (including 66 patients with CC and 115 of their relatives), of different ethnicity, living in the Republic of Bashkortostan. Results. The average prevalence of KC during the study period was 6.7, and the incidence according to the data of the appeal was 2.0 per 100,000 population. The highest prevalence rates occurred among such nationalities as Chechens (0.36 %), Azerbaijanis (0.17 %) and Armenians (0.15 %). As a result of molecular genetic studies, single nucleotide substitutions in the SOD1 gene were identified: rs16988404, rs2234694 not previously described in patients with KC. The frequency of the minor allele in the sample of patients was 6.1 % and 3.0 %, respectively. Conclusion. The high incidence and prevalence of KC in the Republic of Bashkortostan among people of working age with significant ethnic (predominance among Caucasian nationalities) was revealed and gender (2 times more often in men) segregation. In a quarter of cases, hereditary forms of KC occur. A number of the most informative keratobiometric parameters in the diagnosis were revealed: the irregularity of the cornea in the 3 mm zone, the thickness of the cornea in the center, at the thinnest point, the maximum elevation of the anterior surface, as well as the elevation indicators of the posterior surface. Keywords: keratoconus, epidemiology, diagnosis, treatment, Republic of Bashkortostan

Molecular genetic aspects of Gilbert's syndrome, Crigler-Najjar syndromes types I and II

Variants of the UGT1A1 gene are associated with impaired bilirubin metabolism, which is clinically expressed in Gilbert's syndrome (GS), Crigler-Najjar syndrome types I and II, as well as increased toxicity intaking certain drugs (indinavir, irinotecan, atazanavir, sorafenib, tocilizumab, belinostat, and paracetamol). A common manifestation of these conditions is unconjugated hyperbilirubinemia. The most common variant in the UGT1A1 gene associated with GS (the most common pathology caused by UGT1A1 gene variants) is the UGT1A1*28 variant, which is an increased number of TA repeats in the promoter of the UGT1A1 gene up to 7. However, the UGT1A1*28 variant is not the only gene variant capable of causing unconjugated hyperbilirubinemia. It is known that the variants UGT1A*7, UGT1A*6, and UGT1A*27 were found in the Asian population, which also causes GS with a high frequency. For Caucasians, the UGT1A1*28 variant remains the only common variant that causes GS. At the same time, even the carriage of the UGT1A1*28 variant in the homozygous state does not always lead to the appearance of clinical symptoms. While in the heterozygous form of the UGT1A1*28 variant, high unconjugated hyperbilirubinemia can be observed. Thus, other molecular genetic markers probably explain the incomplete penetrance and variable expressivity of the clinical manifestations of the UGT1A1 gene variants

Integrated clinical genotype-phenotype characteristics of early T-cell precursor acute lymphoblastic leukemia.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T-ALL with a unique immunophenotype and high treatment failure rate. The molecular genetic abnormalities and their prognostic impact in ETP-ALL patients are poorly understood. The authors performed systematic analyses of the clinicopathologic features with an emphasis on molecular genetic aspects of 32 patients with ETP-ALL. The median age was 43years (range, 16-71). The blasts were positive for cytoplasmic CD3 and CD7 and negative for CD1a and CD8. Other markers expressed included CD34 (88%), CD33 (72%), CD117 (68%), CD13 (58%), CD5 (partial, 56%), CD2 (38%), CD10 (25%), CD56 (partial, 19%), and CD4 (6%). Cytogenetic analyses revealed a diploid karyotype in 10 patients, simple (1-2) abnormalities in 10 patients, and complex karyotype in 10 patients. Next-generation sequencing for 21 patients demonstrated that all had gene mutations (median, four mutations per patient). The most frequently mutated genes were WT1 (38%), NOTCH1 (29%), NRAS (29%), PHF6 (25%), TP53 (24%), ASXL1 (19%), FLT3 (19%), and IKZF1 (19%). All patients except one received multi-agent chemotherapy, and 22 patients underwent allogeneic stem cell transplantation. Thrombocytopenia, an abnormal karyotype, and TP53 mutation were associated with markedly shortened overall survival. Stem cell transplantation significantly improved overall survival. Patients with ETP-ALL often have high mutation burden with increased genomic instability. TP53 mutation was the only molecular prognostic marker and was associated with complex karyotype and greater than or equal to five mutations. These patients may benefit from stem cell transplantation, and recurrent gene mutations may be novel therapeutic markers.