Medullary thyroid carcinoma (MTC) is a relatively rare malignancy (approximately 2–5% of all thyroid cancers) characterized by an aggressive clinical course. Activating mutations of the RET (REarranged during Transfection) proto-oncogene play a key role in MTC pathogenesis, being present in all hereditary cases and about half of sporadic cases, and these genetic alterations represent critical targets for targeted therapy. This review summarizes current data on the spectrum of RET gene mutations in MTC and evaluates their significance for targeted therapy. The most common RET mutations (such as point mutations p.Met918Thr and p.Cys634Arg) as well as chimeric rearrangements (fusions) of the RET gene are described, and their association with tumor sensitivity to targeted therapies is discussed. Approaches to therapy selection based on the tumor’s molecular profile are considered, including the use of first-generation RET tyrosine kinase inhibitors (multi-kinase agents, e.g., vandetanib and cabozantinib) and highly selective second-generation RET inhibitors (e.g., selpercatinib and pralsetinib). Special attention is given to the role of molecular genetic testing of RET in optimizing MTC treatment. In conclusion, the need for a personalized approach with molecular stratification of MTC patients by RET status is emphasized, and the promise of new targeted agents directed at various RET mutations is highlighted.

Fibrodysplasia ossificans progressiva (FOP, MIM135100) is a rare autosomal dominant disease characterized by the appearance of foci of spontaneous ossification in soft tissues of various localization in the patient. Pathogenic variants occurring in the ACVR1 gene are responsible for the development of this pathological conditions. From 2009 to 2024, a diagnostic examination of 158 people with suspected FOP using direct automatic Sanger sequencing was conducted. The cause of the disease was identified in 68 (43%) of the samples. Based on the analysis of the patients’ ages, the incidence of Fibrodysplasia ossificans progressiva in the Russian Federation was estimated. It was at least 1,656 per million or 1 per 604,000 newborns.

Introduction. Early diagnosis and prevention play a key role in providing primary care to patients with hereditary diseases. However, not all diseases for various reasons, including severe neuromuscular pathology – Duchenne/Becker muscular dystrophy (DMD/BMD), can be detected today in the neonatal period in the Russian Federation.
Aim: to test the system of two-stage screening of DMD/BMD in children of the 2nd year of life in St. Petersburg for further implementation in the healthcare system of the city of St. Petersburg.
Methods. Venous blood samples from 1878 boys were studied step by step using the following methods: IFCC, MLPA, СMA.
Results. In 2024, 4 patients with pathogenic variants in the DMD gene were identified – 1 patient as a part of the screening system and 3 patients due to the orphan alertness of doctors and the inclusion of these patients in the pilot program.
Conclusions. The preliminary results of the pilot screening of the examined patients confirm the prospect of the proposed two-stage screening program for the early diagnosis of Duchenne/Becker muscular dystrophy.

Identification of SNPs related to manifesting excessive aggressive behavior based on calculation of polygenic score (PGS) and a relevance of extrapolation of GWAS data obtained in European cohorts to a sample of Russian residents is of interest. The present study aimed to design regression models explaining variance in aggression level in Russian cohort and including PGS and social parameters as predictors. The study comprised of individuals from Russia aged 18-25 (N=1065, 80% women) who underwent psychological testing using the BPAQ questionnaire to assess aggression level. We performed genotyping of 30 SNPs in the genes belonging to monoaminergic, hypothalamicpituitary-adrenal and inflammatory systems, and genes involved in epigenetic regulation. Regression models were identified, which explain up to 13.3% of variance in physical aggression (p=2.2*10^-16), including PGS (SNPs in CRP, TNF, IL1A, AVPR1A, OXTR, TERC, MIR2113, MIR124, MIR135A2, FYN, DRD4, and SLC6A4 genes) and social factors such as family income, birth order, maternal protection, and current smoking as predictors. The data obtained support the genetic similarity of the molecular mechanisms underlying the development of physical and verbal aggression and antisocial and risky behavior.

Modern oncogynecology research is aimed at screening molecular diagnostic markers of ovarian cancer (OC). The aim of the study was to identify new potential non- and minimally invasive molecular markers of OC using omics technologies. The study included 300 patients with OC and 50 conditionally healthy volunteers. Urine and blood plasma were used for analysis. Separation of metabolites was performed on a Vanquish Flex chromatograph and an Orbitrap Exploris 480 mass spectrometer. The miRNA level was determined by the RT-PCR method. In patients with OC, significant changes in the blood plasma and urine metabolome were detected, and abnormal levels of miRNAs were detected in urine and plasma, some of which (miR-33b-5p, miR-423-5p, miR-6743-5p, miR-4668-3p, miR-23a-3p, miR-4502, miR-17-5p, miR-320a-3p, miR-330-5p) have potential as non- and minimally invasive OC markers.

The results of analyzing the efficiency of mass parallel sequencing methods for the diagnosis of hereditary arthrogryposis on the basis of a cohort of 227 patients are presented. It is shown that the use of a target gene panel, whole exome or genome sequencing allows to confirm the diagnosis in 69% of patients with clinical signs of arthrogryposis. The proportions of specific nosological groups of hereditary arthrogryposis were estimated. It was revealed that the neuromuscular arthrogryposis represents 42% of all diagnosed arthrogryposis, of which 76% are myogenic.

Background. Choroideremia (CHM, OMIM303100) is a rare (1:50 000 men) hereditary disease, with an X-linked, recessive type of inheritance. Leads to significant loss of vision against the background of primary damage to the choriocapillary layer of the vascular membrane with subsequent progressive atrophy of the retinal pigment epithelium (RPE) and photoreceptors.
Purpose. To present the features of the phenotypic manifestations of choroideremia in carriers of a mutation in the CHM gene in childhood.
Methods. The article describes a clinical case of choroideremia with a mutation in the CHM gene in two sisters aged 4 and 6, whose parents went to an ophthalmologist complaining of decreased distant vision in their eldest daughter. In addition to the standard ophthalmological examination, patients underwent spectral OCT and electrophysiological examinations. To verify the diagnosis and identify the pathogenic nucleotide sequence of the gene, a molecular genetic study was performed with a preliminary collection of family history.
Results. A family history and a comprehensive examination of the blood relatives of this family in 3 generations established the Х-linked type of inheritance of the disease. The girls’ corrested visual acuity was 0.9. The high visual acuity of the patients correlated with the state of the fovea according to spectral OCT, which retained a three layered structure: the Bruch’s membrane – PES – the outer boundary membrane. The line of articulation of the outer and inner photoreceptors segments was absent on the periphery of the scan, but remained within the fovea. Electrophysiological examination was difficult due to the patients’ age. A genetic examination of the family members revealed a previously undescribed pathogenic variant of the nucleotide sequence in exon 10 of the CHM gene, leading to the appearance of a premature translation termination site in codon 445 (p.Ser445*) which is inherent in such a form of IRD as choroideremia.
Conclusion. Thus, the genetic examination made it possible to correctly verify the form of IRD – choroideremia. Carriers of the pathogenic variant of the nucleotide sequence in exon 10 of the CHM gene, even in childhood, have signs of chorioretinal degeneration, detected by OCT and electrophysiological data.

Since January 2023 expanded neonatal screening (ENS) has been carried out in the Russian Federation, including the determination of TREC/KREС markers, which allow one to suspect primarily severe combined immunodeficiency (SCID) and agammaglobulinemia (AGG) before the development of severe infectious complications. Screening revealed a boy with a decrease in KREC to 0 copies/105 cells and a marked decrease in the number of B-lymphocytes. Whole exome sequencing revealed a hemizygous pathogenic variant in the BTK gene, which was previously described in patient with X-linked agammaglobulinemia, type 1. The child was born as a result of in vitro fertilization using donor oocyte. Given the development of genetic technologies, the introduction of preconception screening for gamete donors is a reasonable prospect which however requires further investigation.

The spectrum and frequency of filaggrin (FLG) gene variants were analyzed in indigenous Bashkir and Tatar populations of the VolgaUral region of Russia. Whole-genome sequencing identified 153 FLG variants, four of which are loss-of-function mutations (rs567795279, rs61816761, rs200519781, rs558269137). The c.2282_2285del (rs558269137) deletion in the FLG gene was found to be the most common variant in the studied populations. Previous studies have associated this deletion with the development of allergic diseases in individuals of Russian, Tatar, and Bashkir ethnicity.

Preeclampsia (PE) is a severe disorder with varying incidence and severity across modern human populations. Defects in the maturation of placental decidual cells (DC) are known to contribute to endothelial dysfunction and the development of PE. In this study the analysis focused on identifying commonalities and specificities in DC expression profiles across populations in normal pregnancy and PE, as well as assessing the impact of interpopulation differences on overall gene expression variability.

Polymorphism of genes encoding proteins of DNA repair systems was studied in three groups of patients with various cardiovascular diseases (CVD) in comparison with a population sample and a group of long-livers. Regression analysis revealed statistically significant differences between all groups for rs560191 of the TP53BP1 (p=4.01E-4) gene and rs1801516 of the ATM gene (p=1E-7). Pairwise comparisons of samples revealed differences in the ATM gene between the group of centenarians and patients with both chronic coronary heart disease (rs1801516: p=0.027 (alleles) and p=0.040 (genotypes)) and ST-segment elevation myocardial infarction (rs1189037: p=0.017 (alleles) and p=0.027 (genotypes)). The obtained differences prompt us to pay closer attention to the studied group of genes in the context of their involvement in the predisposition to CVD.

The associations of gene polymorphism (APEX1 rs1130409, hOGG1 rs1052133, XRCC1 rs25489, XPD rs13181) were studied in 210 women living in the Kemerovo region diagnosed with breast cancer and 224 healthy women from Kuzbass, who formed a comparison group. Associations of breast cancer with the APEX1 rs1130409 for the log-additive inheritance model (OR=0.74; 95% CI=0.57–0.97; p=0.03) and hOGG1 (rs1052133) for the dominant inheritance model (OR=1.54; 95% CI=1.05–2.27; p=0.02) were revealed. 

 There is currently no neuroprotective therapy for Parkinson’s disease (PD). PD associated with mutations in the GBA1 gene (GBA1-PD), which is the most common form of PD with a known etiology, is considered the most promising for the development of target therapy. Currently, clinical trials of pharmacological chaperones (PC) aimed at increasing the activity of glucocerebrosidase (GCase), encoded by the GBA1 gene, as well as inhibitors of leucine-rich repeat kinase 2 (LRRK2) are underway for the treatment of PD. In this study, we compared the efficacy of the LRRK2 kinase inhibitor, MLi-2, with the known PCs of GCase, ambroxol and NCGC00241607 (N07), in restoring GCase activity in primary culture of macrophages from patients with GBA1-PD. 

A search of natural selection signals was performed in genomic loci associated with the severity of COVID-19 in 10 Caucasian populations. MALDI-TOF mass spectrometry technology was used for multiplex genotyping of 45 SNP markers. When assessing the selective neutrality of the studied genetic markers using the Evens-Watterson test, deviation from neutrality was found for 8 SNPs. 

Background. Analysis of non-coding regions of the genome, sufficiently covered in whole exome sequencing (WES) data, may improve the diagnosis of hereditary diseases.
Objective: To assess the frequency and spectrum of clinically significant variants in intronic and other non-coding regions identified in WES data, and to review patient diagnoses.
Methods. The study included 691 patients. DNA was extracted from venous blood, and WES was performed using Agilent All Exon v8 probes and the G-400 platform (MGI Tech). Data analysis included quality control, read processing, variant calling, and annotation. Only clinically significant non-coding variants were selected.
Results. A total of 18 unique variants in 17 genes were identified in 31 patients (4.49%), all in heterozygous states, with the most frequent variants found in SPTA1, HGD, and GAA. The diagnosis was revised for one (0.145%) patient with POLR3A variants leading to leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism.
Conclusion. Clinically significant variants in non-coding regions (beyond the canonical ±1-2 splice sites) should be considered during WES data interpretation.

DNA methylation changes play an important role in aortopathies. However, the methylation status of genes of hereditary thoracic aortic aneurysms in patients with aneurysm, atherosclerosis and their combination remains unclear. DNA methylation of 53 genes was assessed using the RRBS method in the atherosclerotic plaque, dilated and non-dilated aorta of the patients with sporadic thoracic aortic aneurysm and tricuspid aortic valve. We also performed a comparative analysis of own and external data. It was shown that in patients with aneurysm in the atherosclerotic plaque relative to the non-dilated aorta, differential methylation affects the regions of enhancers of the NOTCH1 and GATA5 genes.

We investigated the role of the cumulative effect of rare high-impact (HI) genetic variants in Notch pathway gene sets on the development of anemia in two cohorts of patients at high risk for chronic or acute critical illness: patients with traumatic brain injury (TBI) admitted for rehabilitation and patients with acute COVID-19. In both patient cohorts, an association was found between the risk of severe/moderate anemia and the cumulative effect of HI variants in Notch pathway genes. In patients with COVID-19, HI variants in Notch pathway genes affected RBC, HGB, and HCT levels. 

Introduction. The demographic crisis in Russia has significantly exacerbated the issue of infertile marriages and highlighted the growing use of assisted reproductive technologies (ART). However, their application cannot automatically guarantee the birth of healthy children.
Objective. To screen for heterozygous carriers of severe hereditary pathologies among infertile couples.
Methods. Testing was conducted on 330 married couples for 51 monogenic diseases using next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA).
Results. A total of 301 heterozygous carriers were identified. The highest carrier rates were observed for congenital hearing loss (66 heterozygous carriers), biotinidase deficiency (57 carriers), alpha-1-antitrypsin deficiency (28), cystic fibrosis (25), and limb-girdle muscular dystrophy (21). In four couples, both parents were carriers of the same pathogenic gene variant; all received genetic counseling on currently available options to minimize the risk of having an affected child.
Conclusions. The results indicate a high prevalence of genetic pathology carriers among these couples, justifying further systematic screening for people by reproductive age.

Proteins with chaperone activity, including the recently discovered class of Hero proteins, are involved in the pathogenesis of viral infections, the development of the immune response, and the maintenance of homeostasis. To study the association of the rs2900262 polymorphism of the C9orf16, encoding a protein belonging to the Hero class, we performed genotyping of single nucleotide polymorphism in 898 unrelated individuals from Central Russia, including 199 patients with severe COVID-19. It was found that the T allele of rs2900262 C9orf16 correlates with a decrease in activated partial thromboplastin time (APTT) in males, indicating the prevalence of thrombus formation processes. It was also found that this polymorphism is associated with fewer days on O2 and a decrease in the C-reactive protein (CRP) count in the group with low fruit and vegetable intake.

A fungicide from the phthalimide class exhibited cytotoxic and genotoxic effects on human peripheral blood lymphocytes in vitro. At the pesticide concentration of 2.5-25 μg/ml, an increase in the pool of cells in late apoptosis and necrosis was observed. The effect depended on the concentration and the exposure time. An increase in the level of DNA damage in the cells of some donors was noted already at concentrations of 5-12.5 μg/ml. At 25 μg/ml, a statistically significant increase in the «% DNA in the tail comet» parameter was found in lymphocyte of 47 out of 48 donors.

Bronchial asthma (BA) and pulmonary tuberculosis (TB) are multifactorial diseases and pose an important public health problem. Susceptibility to these diseases is based on both environmental and genetic factors, most of which are unknown. The study examined the association of 13 polymorphic variants of genes that affect the implementation of the immune response in samples of patients with BA, TB and in the control group. Two statistical algorithms were used: univariate analysis of associations and classification of genetic data using the decision tree algorithm. The study found that rs525891, rs2239704, rs16944, rs1800872, rs56061981 and rs4386624 variants are associated with TB, and rs2239704, rs652625 are associated with BA.

The similarity of pathogenesis mechanisms for pregnancy loss, preeclampsia, fetal growth restriction, and preterm birth due to abnormal placentation suggests the existence of common methylation patterns for various pathologies. Therefore, the aim of this study was to conduct a comparative analysis of DNA methylation abnormalities and their association with protein expression in chorionic villi from spontaneous abortions. The DNA methylation profiles of chorionic villi in cases of pregnancy loss and the aforementioned pathologies were obtained using reduced representation bisulfite sequencing and data sets from the Genome Expression Omnibus, respectively. Gene expression was determined by immunohistochemistry. The only commonly hypermethylated gene among the studied pathologies was CLEC16A. For spontaneous abortions (SA), 237 differentially methylated genes (DMGs) were identified. The GLI3, EGFR, CMIP, and PBRM1 genes showed differential expression in the chorionic villi of SA samples. Thus, a significant number of SA-specific DMGs were associated with changes in their expression. The functions of these identified genes suggest their role in the formation of lethal phenotypes.

Background. Induced pluripotent stem cells (iPSCs) serve as an important model for studying the processes of embryogenesis and genetic diseases. At the same time, iPSCs are characterized by elevated levels of replication stress and genetic instability during mitosis. Under conditions of replication stress, breaks occur in the chromosomal material at constitutive fragile sites (CFS), which are observed on metaphase plates. Mapping CFS in iPSCs helps to better understand the functional consequences of replication stress for the derivatives obtained from iPSCs, as well as the mechanisms underlying somatic mutagenesis (including those occurring during the embryonic period). The current study continues the work on mapping constitutive fragile sites in human induced pluripotent stem cells in the context of investigating their genetic stability and safety.
Aim. Molecular mapping of constitutive fragile sites in iPSCs using FISH probes marking the boundaries of long genes.
Methods. Human iPSCs were cultured using a feeder-free method. Induction of chromatid breaks was performed by adding aphidicolin and caffeine to the medium. FISH probes specific to the boundaries of the studied genes were obtained using long range PCR and nick translation.
Results. The target genes were selected based on their size within the boundaries of the chromosomal bands where chromatid breaks were observed following treatment with replication inhibitors. Fluorescent signals from FISH probes specific to the boundaries of the genes ANKS1B, LRP1B, WWOX, NRXN3, LINGO2, and PRKN were detected on either side of the chromatid break, indicating the localization of the CFS within the target gene.
Conclusion. Replication instability has been revealed in iPSCs for six clinically significant genes that are functionally associated with oncogenesis and the development and functioning of nervous tissue. These results may clarify the role of replication stress in the formation of somatic mosaicism during embryogenesis. Additionally, mutations in these genes may affect the functional viability of differentiated derivatives of iPSCs.

Introduction. Prevention of hereditary and congenital pathologies is the main goal of institutions and departments of medical genetic services.
Aim: to optimize genetic diagnostics of hereditary diseases in a multidisciplinary children’s clinic.
Methods. Patients were hospitalized in the departments of Scientific and Practical Center of Specialized Medical Care for Children. Patients’ age was from 0-17 years. Clinical and genealogical analysis, as well as molecular genetic studies (Sanger sequencing, whole exome sequencing) were performed in patients in order to describe the clinical picture of the disease.
Results. The need for genetic testing of children with congenital and hereditary diseases was 25,3%. The diversity of hereditary diseases was established based on the results of the study and analysis. The capabilities of the genetic laboratory are shown and the use of methods of molecular genetic diagnosis in children is scientifically justified. The clinical effectiveness of whole exome sequencing was 73,3%.
Conclusion. The spectrum of identified nucleotide sequence variants in genes responsible for hereditary and congenital pathologies was analyzed as part of the implementation of the strategy for the development of molecular genetic diagnostics. Recommendations were given to doctors on the effectiveness of treatment, and individual rehabilitation programs were developed based on the obtained data and identified options.

Introduction. Single nucleotide polymorphisms (SNPs) rs4373814 (CACNB2), rs12940887 (ZNF652), rs10850411 (TBX3) are associated with hypertension (HTN) risk, and as part of genetic risk score (GRS) with predisposition to coronary artery disease (CAD).
Aim: to establish the role of these SNPs in the efficacy of rosuvastatin and studying their individual association with CAD and HTN risk.
Methods. 1960 residents of Central Russia were enrolled in CAD and HTN risk study (91% of CAD patients had HTN), 116 CAD patients – in pharmacogenetic study. We assessed total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) change after 1, 6, and 12 months of rosuvastatin therapy. Genotyping was performed on the MassArray-4 System. SNPs association with CAD and HTN risk, and with lipid levels change was estimated by logistic and linear regression, respectively using PLINK v1.90.
Results. Reduced TC-lowering effect of rosuvastatin was associated with rs4373814, rs12940887 (p = 0.019 and 0.014, respectively), and reduced LDL-C-lowering effect – with rs12940887, rs10850411 (p = 0.049 и 0.023, respectively). All SNPs were not associated with CAD risk (p>0.05). The risk of HTN was linked to rs4373814 (p = 0.038).
Conclusions. The association of HTN and CAD (as part of GRS)-associated loci with rosuvastatin pharmacogenetics was established for the first time.

High research interest in the polymorphism of the VDR and NFKB genes is due to its ability to modify intracellular signaling, determine the adaptive potential of populations and affect the structure of population morbidity. The data of a study in a sample of the Russian population of Siberia of the frequencies of haplotypes of the VDR and NFKB1 genes for a panel of 13 SNPs are discussed. DNA isolated from blood samples (n = 96) was genotyped by real-time PCR. The result was the identification of 21 haplotype variants in the VDR and 33 in the NFKB1. The frequency and spectrum of major haplotypes recorded with a frequency of more than 20%, as well as common variants found in the gene pool of Russians in Siberia with a frequency of more than 5% and more than 1% were established. The data obtained characterize the gene pool of the Russian population of Siberia and can be used as a basis for subsequent studies.

Anomalies of the auditory nerve (AN) is a significant obstacle to the auditory and speech rehabilitation of the child. Hypoplasia/aplasia of the AN can cause both isolated hearing loss and be detected as part of hereditary syndromes. Objective: to assess the proportion of hereditary etiology in a group of children with hypo-/aplasia of the AN. Genetic counseling was carried out for 16 children with bilateral hypo-/aplasia of the AN, who underwent cochlear implantation (CI). Isolated forms of bilateral hypo-/aplasia of the AN were established in 6 children, 10 children have signs of syndromes, including CHARGE syndrome in 4 children, X-linked stapes fixation syndrome – 1, Noonan syndrome – 1, and 4 children with undifferentiated syndromic forms. Whole exome sequencing revealed pathogenic variants of the CHD7 gene in 3 children and confirmed CHARGE syndrome, one child had variant of unknown significance in the EFTUD2 gene (mandibular-facial dysostosis with microcephaly), another had a pathogenic variant in the POU3F4 gene, and the third had a variant of unknown significance in the GNAO1 gene (neurodevelopmental disorder with involuntary movements). No pathogenic or likely pathogenic variants were detected in 6 children with isolated hypo-/aplasia of the AN. In all cases, the detected variants were consistent with the clinical picture. No pathogenic or likely pathogenic variants were detected in the remaining patients, including 6 children with isolated hypo-/aplasia of АN. Genetic heterogeneity in hypoplasia/aplasia of AN is shown. Half of the children in the examined group had syndromic forms of hearing loss, which allows early detection of such children. According to our results, patients with CI received a significant advantage that allowed them to develop and optimally use new social communication skills.

The results of the analysis of defects in test forms with dry blood spots of newborns sent from medical organizations to the GBUZ RMGTS for neonatal screening (NS) and extended neonatal screening (ENS) are presented. In order to objectify the assessment of defects in test forms and the early detection of congenital and hereditary diseases, an algorithm for interaction with medical organizations during the admission of dry blood stain, for laboratory diagnostics within the framework of NS and ENS, is proposed.