This study substantiates the economic and clinical efficacy of a cascade (stratified) testing approach in molecular genetic diagnostics of hereditary disorders compared to using whole-genome sequencing (WGS) as the first-line diagnostic method. By analyzing the cost, turnaround time, and diagnostic yield of 1,140 strategies across 9 disease groups (cystic fibrosis (CF), phenylketonuria (PKU), Duchenne/ Becker muscular dystrophy (DMD/BMD), spinal muscular atrophy (SMA), hearing loss, hemophilia, hereditary spastic paraplegias (HSP), Noonan/Leopard syndromes, and ultra-rare/heterogeneous disorders), we demonstrate that the optimal strategy strictly depends on the causative variant spectrum of the pathology. For diseases with known frequent pathogenic variants (PKU, hearing loss) or a predominance of large copy-number variations (CNVs) starting with «traditional» methods is economically and clinically justified. For highly heterogeneous conditions an earlier transition to NGS panel sequencing or clinical/whole exome sequencing (CES/WES) is warranted. Cascade testing achieves diagnostic yield comparable to WGS while reducing costs up to 92% and shortening time up to 53 days per 100 samples. No universal optimal method exists; algorithm selection should be based on disease-specific characteristics and resource constraints.

Methylmalonic Aciduria (MMA) and propionic aciduria (PA) are rare autosomal recessive disorders of organic acid metabolism. Early diagnosis of these conditions is crucial for the timely initiation of therapy and improved prognosis. Since 2023, the Russian Federation has implemented an expanded newborn screening (NBS) program that includes MMA and PA. Between 2023 and 2024, a total of 2,466,615 newborns were screened. Primary screening using tandem mass spectrometry identified 7,297 neonates at risk for MMA or PA. Confirmatory molecular genetic testing revealed pathogenic or likely pathogenic variants in 28 patients. Of these, 26 newborns were diagnosed with MMA, and 2 newborns were diagnosed with PA. This study established, for the first time, the incidence of MMA and PA in the Russian Federation. The estimated incidence of MMA was 1 in 95,000 newborns (95% CI: 1 in 69,000–1 in 131,000), while the incidence of PA was 1 in 1,234,000 (95% CI: 1 in 409,000–1 in 3,730,000). The positive predictive value (PPV) of the initial screening for MMA and PA was 0.38%. In 38% of MMA patients, the disease manifested during the neonatal period as a metabolic crisis. Previously unreported pathogenic variants were identified in the MMUT, MMAA, MMACHC, and PCCB genes. The implementation of NBS in the Russian Federation has significantly enhanced the early detection of MMA, enabling timely therapeutic intervention. In contrast, the detection rate of PA was lower than expected compared to selective screening data, highlighting the need to optimize primary screening algorithms and confirmatory diagnostic procedures for this disorder. The study also included analysis of the sensitivity and specificity of additional biochemical markers. An optimized confirmatory diagnostic algorithm was proposed to enhance the efficacy of neonatal screening.

Background. One of the known mechanisms of development and progression of type 2 diabetes mellitus (T2D) is oxidative stress. As an enzyme of glutathione metabolism, aminopeptidase ANPEP plays an important role in the body’s antioxidant system.
Aim: to analyze the contribution of polymorphisms of the ANPEP gene and environmental risk factors to the formation of predisposition to T2D.
Methods. The study included genomic DNA samples obtained from 1579 T2D patients and 1627 healthy volunteers. Genotyping was performed using MALDI-TOF mass spectrometry (MassARRAY Analyzer 4, Agena Bioscience) and real-time PCR (CFX 1000, Bio-Rad). Statistical processing of the obtained data was carried out using the online programs SNPStats, PLINK, MBMDR.
Results. A protective effect of the combination of carriage of the rs12148357, rs25653 and rs11073891 polymorphisms of the ANPEP gene and the absence of smoking and psycho-emotional stress, consumption of normal amounts of fats, carbohydrates, fiber and fresh plant foods was established. At the same time, rs9920421 and rs7111 are associated with an increased risk of developing T2D only in combination with a high-calorie diet and protein deficiency in food. A total of 5165 significant two-locus models of gene-environment interactions associated with the risk of developing T2D were identified (84.8% of the models were SNPs and 15.2% were environmental factors).
Conclusion. Environmental factors modulate the risk of developing T2D in carriers of ANPEP gene polymorphisms. At the same time, polymorphic variants of ANPEP and other genes regulating redox homeostasis closely interact with T2D candidate genes and environmental factors in determining the risk of developing T2D.

Background: Ovarian cancer remains one of the most common causes of death from gynecological cancer in women worldwide. Aim: analysis of the association of polymorphic loci of the rs1625895 и rs1042522 of gene TP53 with the risk of developing ovarian cancer. Material: DNA samples isolated from the peripheral blood of 239 patients with ovarian cancer and 271 conditionally healthy women. Method: PCR-RFLP analysis and real-time PCR. As a result of study, we did not find an association of polymorphic loci rs1625895 and rs1042522 of the TP53 gene with the risk of developing ovarian cancer.

A case of molecular cytogenetic diagnosis of de novo complex chromosomal rearrangement (CCP) in a patient with congenital malformations and psychomotor development delay is presented. The use of molecular cytogenetic methods revealed that CCP is more complex than was proposed by standard cytogenetic diagnosis.

Mitochondrial diseases are a heterogeneous group with a progressive course and a high probability of lethal outcome. Pyruvate dehydrogenase complex deficiency (PDHd) is one of the few mitochondrial diseases with pathogenetic therapy in the form of ketodiet and thiamine supplementation. We present the experience of the Almazov National Research Medical Center, where 7 patients with PDHd are observed. The ketodiet was administered in 6 cases; one child with neonatal lactic acidosis died before diagnosis. Two children started the diet parenterally in the ICU, three were inpatient for a week, and one was outpatient for a month. Target blood ketone and lactate levels were achieved in all cases. Two children with neonatal lactic acidosis were stabilized and discharged. One showed developmental progress while the other had no psychomotor development and developed seizures. A girl with epileptic encephalopathy improved neurologically with the diet, but seizures persisted. Three girls with cerebral palsy had the best therapeutic response, two began walking. The target ketone level was achieved with different keto ratios and different proportions of medium-chain triglycerides in the diet. Ketodiet is an effective treatment method for PDHd. The best result is achieved with early initiation of therapy and with a milder clinical phenotype.

Not all GBA1-carriers develop Parkinson’s disease (PD) during their lifetime. Previously, we identified alterations in gene expression profile of the PI3K/AKT/mTOR signaling pathway in the brain cells of mouse model of parkinsonism with GCase dysfunction by transcriptome analysis. In the current study orthogonal validation of transcriptome data revealed increased DDIT4 gene expression in peripheral blood mononuclear cells from GBA1-Carriers compared to GBA1-associated PD patients, that may be considered as a potential modifier of PD among carriers of mutations in the GBA1 gene.

The study of nonimmune hydrops fetalis (NIHF) is an important issue due to the high risk of adverse pregnancy outcomes. The aim of this work was to evaluate the diagnostic value of whole exome sequencing (WES) in the diagnosis of NIHF causes. WES was performed in 44 patients with NIHF. Pathogenic and likely pathogenic variants, which associated with the clinical phenotype, were found in 20 of 44 (45.5%) fetuses. This data made possible to choose further pregnancy management. The results of the work showed a high contribution of monogenic disorders to the etiology of NIFH.

Hypertrophic cardiomyopathy (HCM) is a common hereditary disease with clinical polymorphism. The aim of the study was to explore the association of sarcomeric genes polymorphisms with the echocardiographic parameters in patients with HCM. Associations were found for the common haplotypes in TPM1 and TNNT2 with phenotype (age of onset, hypertrophy and ejection fraction of left ventricule), which allows us to suggest the modifying effect of these haplotypes for HCM.

Spinocerebellar ataxia type 8 (SCA8) is a rare autosomal dominant disorder caused by CTG repeat expansions in ATXN8OS/ATXN8 genes. Diagnosis of SCA8 is challenging due to clinical heterogeneity of hereditary ataxias and limitations of traditional methods. The aim of this work was to evaluate the efficacy of WGS for diagnosing SCA8 and to describe clinical cases. Patients with suspected hereditary ataxia were included. WGS was performed on the DNBSEQ-T7 platform, followed by bioinformatic analysis including STRipy for repeat expansion detection. Three families with pathogenic CTG expansions in ATXN8OS were identified. Results align with published data on variable penetrance and the influence of maternal transmission on phenotypic severity. WGS demonstrated high diagnostic efficacy for SCA8, enabling simultaneous analysis of multiple loci.

Aim: to clarify the diagnosis using a thorough study of the clinical picture and molecular genetic diagnostic methods in a complex clinical case of a combination of retinal pathology and kidney disease.
Methods. A 17-year-old patient with a presumptive diagnosis of retinal dystrophy had a complete clinical examination, including laboratory and instrumental studies. Сlinical exome sequencing by NGS (next-generation sequencing).
Results. The patient was diagnosed with retinal hypoplasia, normal motor and psychomotor development, stage 2 chronic kidney disease, small kidney cysts and morphological changes characteristic of nephronophthisis1. A deletion of the entire NPHP1 gene in a homozygous state was detected, which allowed for differential diagnosis with diseases with similar clinical manifestations and confirmed the diagnosis of Senior-Loken syndrome 1 in the patient. Analysis of segregation revealed that the mother carried the same deletion in a heterozygous state while the father was not available for analysis.
Conclusion. For successful diagnostics of hereditary diseases with significant genetic heterogeneity, it is necessary to use NGS methods. To confirm deletions and establish the exact boundaries of the rearrangement, it is necessary to conduct whole-genome sequencing.

Background. Exploring the potential of artificial intelligence (AI) and machine learning (ML) is an important task aimed at creating an effective screening strategy, identifying risk groups and using more accessible and cost-effective laboratory tests for the diagnosis of Gilbert syndrome (GS).
Aim. To develop and evaluate the accuracy of a prognostic model for detecting mutations in the UGT1A1 gene based on demographic data (age, gender) and laboratory test results: bilirubin fraction, hemoglobin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
Methods. An anonymized laboratory database was used: 1499 patients, genotypes: 6TA/6TA (n=179), 6TA/7TA (n=496), 7TA/7TA (n=824). The classification model was developed using the LightAutoML platform, combining linear regression and gradient boosting on decision trees.
Results. On the test sample, the developed model showed high diagnostic efficiency in predicting the 7TA/7TA genotype: precision 78%, recall 88%, F1-score 83%. On the validation sample of patients with mechanical jaundice, the model demonstrated high specificity without classifying the 7TA/7TA genotype, which emphasizes its potential for differential diagnosis of hyperbilirubinemia.
Conclusion. The model is promising for clinical use, especially in screening and medical decision support systems (MDSS).

The aim of this study was to investigate the relationship between four functionally significant single nucleotide polymorphisms (SNPs) – rs2236626, rs5751901, rs5760492, and rs28509371 of the GGT1 gene and the development of coronary heart disease (CHD). A comparative analysis of the allele and genotype frequencies of the SNPs rs2236626, rs5751901, rs28509371 among patients with CHD and controls did not reveal statistically significant associations with the development of CHD, both in the overall groups and in the groups stratified by gender (P>0.05). Furthermore, an analysis of metric data assessing the degree of coronary artery stenosis indicated that polymorphisms of the GGT1 gene are associated with a lesser degree of damage to individual coronary arteries, as well as more favorable physiological parameters of myocardial contractility.

Objective: description of a rare case of galactose metabolism disorder in a patient.
Methods: examination of a child with hypergalactosemia was conducted. Molecular genetic testing was performed using clinical exome sequencing and Sanger sequencing.
Results: molecular genetic testing was carried out on a 1 year and 9 months old patient with elevated galactose levels identified through newborn screening. Two variants of the nucleotide sequence of the GALE gene were found in a compound heterozygous state (p.Thr271Met, p.Tyr241His). Medical genetic counseling was provided to the family, Medical genetic counseling was conducted for the family, and the carrier status of the parents was clarified.
Conclusion: establishing an accurate diagnosis will allow timely determination of patient management strategies.

Background. Since oxidative stress plays a role in the pathogenesis of ischemic stroke (IS), it is important to investigate the molecular mechanisms contributing to redox homeostasis and glutathione metabolism.
Aim: to analyze the association of the rs8140505 polymorphism of gamma-glutamyltransferase 5 (GGT5) gene with the risk of ischemic stroke.
Methods. DNA samples from 600 patients with IS and 688 controls were used for genotyping SNP rs8140505 by real-time PCR with allele discrimination using TaqMan probes. 
Results. It was found that genotypes -G/G are associated with an increased risk of IS in females of Central Russia (OR=2,51, 95%CI 1,17– 5,36, Pperm=0,034), while no associations between rs 8140505 genotypes were observed in males.
Conclusion. This study was the first to establish the association of the rs8140505 polymorphism with the risk of IS. Further studies are needed to clarify the nature of the sex-specific SNP association.

Introduction. Symptomatic therapy for Duchenne muscular dystrophy is unable to prevent the development of the disease, so hopes for treating the disease are concentrated in the field of gene therapy, which allows compensating for genetic defects by introducing nucleic acids into the cell.
Aim: study of the properties of cationic and anionic peptides to improve the DNA delivery to muscle cells.
Methods. Methods of C2C12 myoblast cultivation, cell transfection, analysis of toxic properties using a resazurin test, and flow cytofluorometry were used in the work. C57BL/10Jmdx mice were used for in vivo experiments.
Results. Most of the developed complexes are not toxic to C2C12 myoblasts and effectively deliver plasmid DNA to muscle cells both in vitro and in vivo.
Conclusions. The most effective was the nucleopeptide complex containing the largest amount of shielding coating in its composition, which increases its stability in the extracellular matrix of skeletal muscles and, thus, ensures the greatest efficiency of DNA delivery.

Parkinson’s disease (PD) and multiple system atrophy (MSA) belong to a group of synucleinopathies, the pathogenesis of which is based on the aggregation of the alpha-synuclein protein. Mutations in the LRRK2 and GBA1 genes are the most common cause of the development of hereditary forms of PD. In the present study, we estimated the frequencies of mutations in the LRRK2 (G2019S, R1441C) and GBA1 (N370S, L444P, E326K, T369M) genes among 1564 patients with PD, 117 patients with MSA and 400 control individuals in the North-West region of Russia. The level of alpha-synuclein in peripheral blood erythrocytes of patients with PD, MSA, patients with these pathologies who are carriers of mutations in the GBA1 gene, as well as control individuals was assessed. The study showed that mutations in the GBA1 gene are associated with an increased risk of developing PD and MSA, and patients with GBA1-associated PD are characterized by an increased level of total alpha-synuclein in peripheral blood erythrocytes.

Background. Multiple strand displacement amplification (MDA) is the preferred method for whole genome amplification (WGA) in preimplantation genetic testing (PGT) for monogenic diseases (PGT-M).
Objective. To investigate the potential of using MDA-based WGA products for aneuploidy analysis with next-generation sequencing (NGS).
Methods. WGA products from two human blastocyst samples were analyzed using NGS. The WGA process was performed using the REPLi-g Mini Kit (Qiagen), and DNA libraries were generated using the SyntEra-DNA Reagent Kit (Syntol). Bioinformatics analysis was carried out using the Genomenal software (Novel Software Systems).
Results. Based on aCGH and NGS results, molecular karyotypes were generated for blastocysts, which were consistent with minor discrepancies.
Conclusions. The PGA product, obtained using MDA, can be successfully analyzed using NGS, allowing for the use of a single amplicon for both PGT-A and PGT-M applications.

Albinism is a clinically and genetically heterogeneous group of disorders caused by impaired melanin synthesis. There are many genes associated with albinism that have been identified. Isolated and syndromic forms are described. The aim of this study was investigation of the molecular genetic methods effectiveness for the diagnosis of albinism. As a result of the study, it was found that the effectiveness of Sanger sequencing of the TYR gene was 49%, MLPA 7%, targeted panel 21%, whole-exome sequencing (WES) and whole-genome sequencing (WGS) 5% and 18%, respectively. Comprehensive diagnostics of albinism, including TYR gene sequencing, targeted panels, WES, and WGS, is essential for identifying both common and rare forms of the disease, including syndromic cases and structural rearrangements, thereby maximizing the effectiveness of determining genetic causes.

Introduction. Gene therapy is an approach to the treatment of hereditary and multifactorial diseases by delivering nucleic acids into cells. Currently, its prospects for the treatment of endometriosis (EM), a common gynecological disease, have been shown. Gene therapy of EM is possible by inhibiting neoangiogenesis in endometrioid foci by suppressing VEGFA gene expression using RNA interference.
Aim: evaluation of the properties of electrostatically stabilized nucleopeptide complexes as delivery vehicles for anti-VEGF siRNAs in vitro and in rats with surgically induced endometriosis.
Methods. Physicochemical (size, charge, stability), toxic (resazurin test), and transfection (suppression of GFP gene expression) triple complexes of siRNA with arginine-cysteine-rich peptide carrier R6p coated with glutamate-rich polypeptide E6pH-CDP with a ligand to the CXCR4 receptor were studied. A subcutaneous EM model in Wistar rats was used for in vivo experiments.
Results. It has been demonstrated that the developed complexes are non-toxic, resistant to blood serum, and can ensure the delivery of siRNAs to endometrioid foci, stopping their growth.
Conclusions. The results obtained indicate the promise of the R6p/E6pH-CDP carrier modified with a CXCR4 receptor ligand for use as a delivery vehicle for anti-VEGF miRNAs in order to suppress angiogenesis in EM.

Despite extensive worldwide studies of heat shock proteins (HSP) in risk of ischemic stroke (IS), the role of the HSP40 family remains virtually unexplored. Thus, the aim of this work was to study the association of polymorphic variants of the HSP40 genes with clinical parameters of patients with IS. Genotyping of 1306 patients with IS was performed using real-time PCR and the MassArray-4 system. It was observed that rs6500605 DNAJA3 is associated with an earlier age of IS manifestation (β = -1,33±0,64, P perm = 0,03) and a lower level of total cholesterol in the blood (β = -0,42±0,54, P perm = 0,02); rs3731896 DNAJB2 is associated with a decrease in the prothrombin index (PTI) (β = -2,31±0,87, P perm = 0,008) and international normalized ratio (INR) (β = -0,10±0,049, P perm = 0,045). Thus, polymorphic variants of the genes encoding heat shock proteins HSP40 affect the clinical parameters of patients with IS.

The article presents a retrospective analysis of the results of expanded newborn screening (NBS) for inborn errors of metabolism (IEM)
in the Nizhny Novgorod region during 2023–2024. The study aimed to assess the effectiveness of NBS in early detection of IEMs and
improving patient outcomes. Out of 192 patients who required retesting, 4 were diagnosed with IEMs.
All patients with confirmed diagnoses received specialized treatment, including dietary adjustments and medication. A clinical case of a girl with methylmalonic acidemia detected through NBS and presenting with a congenital malformation — a left-sided cleft lip — is presented. During follow-up observations, the patient is developing age-appropriately, has successfully undergone surgical correction for the cleft lip, and continues to receive diet therapy and necessary medications.
The findings underscore the significance of MBS in early identification of IEMs, although maintaining vigilance among healthcare professionals remains crucial, especially when screening results are negative.

There are reported clinical and molecular characteristics of mitochondrial DNA depletion syndrome-5 in a child from the Republic of Sakha (Yakutia). The patient had been included in the risk group of expanded newborn screening before the diagnosis was established. The whole-genome sequencing revealed the variant c.148C>T in the homozygous state, which leads to termination of protein synthesis p.Gln50* in the SUCLA2 gene.

Vulgar ichthyosis (VI) (OMIM #146700, ichthyosis simplex) is the most frequent congenital disorder of keratinization, is relatively mild in clinical manifestations of the whole group of non-syndromal ichthyoses. VI is the most frequent genodermatosis (1:250-1:5300 people). The disease is caused by pathogenic variants in the filaggrin gene (OMIM #135940, FLG). The FLG gene consists of three exons and two introns and is localized in the epidermal differentiation complex gene cluster on the short arm of chromosome 1 (1q21). VI is inherited in a semidominant manner. Both pathogenic variants in the FLG gene in the heterozygous state, in which case the penetrance of the disease is about 90%, and biallelic variants can lead to the development of VI. This study examines the clinical course of VI in a family with features of the disease: a proband homozygous for the variant NM_002016.2(FLG):c.2282_2285del p.(Ser761Cysfs*36) and his parents heterozygous for the proband’s variant.

An examination of two families with reproductive dysfunction was conducted. In both families, the spouses had a normal karyotype based on the results of cytogenetic analysis. The study of the karyotypes of embryos during preimplantation genetic testing revealed the presence of partial aneuploidies in the terminal regions of chromosomes. A molecular cytogenetic analysis was performed using specific DNA probes for candidate subtelomeric regions of chromosomes. The women were found to have a balanced translocation: in the first case, between the terminal regions of chromosomes 1 and 10, and in the second case, between chromosomes 7 and 17.

The mosaic form of hereditary tumor syndromes (HTS) often was not timely diagnosed due to a small percentage of the mutant allele in the blood DNA. We have described a modern algorithm for genetic laboratory diagnostics of HTS using examples of a patients with von Hippel-Lindau syndrome and retinoblastoma, which included the analysis of available primary tumors and verification of the identified pathogenic variant in blood by deep targeted sequencing.

Variants in the APOB gene are associated with the development of familial hypobetalipoproteinemia (FHBL), variants in the PCSK9, ANGPTL3, ANGPTL4, MTTP and SAR1B genes cause phenotypes similar to FHBL. The aim was to investigate the spectrum of variants associated with FHBL and other similar phenotypes in the «NMRC TPM» sample. The study sample: ESSE-RF participants (n = 3070) and patients of the Expert Center for Hereditary Dyslipidemias (n = 3063). Based on NGS data, the above genes associated with lipid metabolism disorders were analyzed, and the genetic risk scale (GRS) values of low-density lipoprotein cholesterol (LDL-C) were evaluated. A total of 20 variants were found in 34 individuals associated with the phenotypes under study, including 10 variants in the APOB gene (10 individuals), 3 in the PCSK9 gene (4 individuals), 3 in the ANGPTL3 gene (3 individuals), and 4 in the ANGPTL4 gene (17 individuals). All variants were detected in the heterozygous state. In 5 individuals, the LDL-C GHR value was below the 10th percentile. The median LDL-C value in the group was 2,31 (1,52 – 3,03) mmol/L. Carriers of variants in the APOB gene had significantly lower LDL-C levels than carriers of variants in other genes: 1.19±0.72 mmol/L and 2.69±1.09 mmol/L, respectively, p<0.001.

The National Genetic Initiative aims to sequence 100,000 whole genomes of Russian citizens from various ethnic groups and geographic regions. WGS data might help revealing genetic variants that do not manifest clinically during testing. Secondary findings include variants in the genes from the American College of Medical Genetics and Genomics (ACMG) secondary findings v.3.2 list (1). Secondary findings were identified in 2.7% of the subjects. Informing the participants about the identified risks is the essential part of the personalized medicine. Here we describe a framework for the genetic consultation of healthy people with high genetic risks and its application on a limited number of participants from the Republic of Bashkortostan.

Technologies of early diagnosis of rare ethno-specific diseases were developed which are especially important in isolated populations with high prevalence of them. In Yakutia autosomal-recessive diseases such as SOPH-syndrome, Neuronal ceroid lipofuscinosis-6A, Mucopolysaccharidosis-Plus Syndrome, 3M-syndrome, NEM type 1, tyrosinemia type 1, and hereditary nonsyndromic deafness type 1 are being researched. Molecular diagnostics of these conditions was developed by using methods: RFLP, RT-PCR, biochips with sensitivity and specificity ~97%. Implementation of these technologies help to conduct population screening, identify carriers, and supports genetic counseling. The database with a registry was created. Further researches aims to expand the range of tested etno-specific variants.

Introduction. The comorbidity of genetic disorders presents a significant diagnostic and therapeutic challenge. Overlapping phenotypic features can complicate differential diagnosis. This article presents a case of so-called «double trouble» – the co-occurrence of Robinow syndrome and Phelan-McDermid syndrome phenotypes in a single patient.
Objective. To identify the genetic cause of the complex phenotype in the proband, as well as to discuss the challenges of differential diagnosis and management strategies for such cases.
Methods. The proband is a 2-year-old girl. The main complaints included delayed psychomotor and speech development, skeletal abnormalities, epilepsy, and facial dysmorphisms. The family history is not burdened with hereditary pathology. The parents are nonconsanguineous. Studies were conducted to determine the concentrations of 7-dehydrocholesterol and 8-dehydrocholesterol (GC-MS), karyotyping, FISH, and whole-genome sequencing.
Results. The proband was found to have a pathogenic variant c.257A>G (p.Tyr86Cys) in the WNT5A gene, associated with autosomal dominant Robinow syndrome, as well as a large deletion of the terminal region of the long arm of chromosome 22, including the SHANK3 gene, associated with Phelan-McDermid syndrome.
Conclusions. This case highlights the diagnostic challenges of comorbid genetic disorders and emphasizes the importance of using modern genetic analysis methods.

In the Republic North Ossetia-Alania (RNO-A), a generalized analysis of data from epidemiological monitoring of congenital malformations, neonatal screening and genetic-epidemiological research of the population of the republic at the hereditary orphan diseases was carried out. The total frequency of congenital malformations of mandatory accounting in RNO-A is higher than the frequency in the regions of the Russian Federation. Based on the results of a study of newborn bloodspot screening data, allelic heterogeneity was identified for phenylketonuria and cystic fibrosis, as well as locus heterogeneity for congenital adrenal hyperplasia. The population of RNO-A is distinguished by a special spectrum of hereditary orphan diseases caused by rare genetic mutations, some of which are extremely rare in other regions of the world and in Russia.

The combined search for genetic causes of intellectual disability in patients with impaired psychomotor development was performed. Comparative genomic hybridization (aCGH) was performed for 1,427 patients, of whom 766 had a balanced karyotype. Whole-exome trio sequencing was performed for 23 families in whom no causative copy number variants (CNVs) were identified. For eight families, variants in the genes ARID1B, CDKL5, DYNC1H1, PMM2, MACF1, MID1, and ZNF292 were identified as a probable cause of intellectual disability.

For the detection of genomic loci associated with polygenic diseases, an alternative to traditional genome-wide association studies is machine learning with feature ranking according to importance contribution to predictive model performance. To implement this approach, it is necessary to address the class imbalance problem caused by differences in the size of case and control samples, and learn how to select features based on their importance metric, which unlike p-values does not have a threshold. This work presents a bioinformatic approach that solves both problems simultaneously. It is based on training a random forest algorithm on randomized case-control samples of similar size, followed by feature ranking according to decreasing importance score and selection based on frequency among top-ranked values, as well as stability of importance scores. The approach has been tested on simulated genotypephenotype data containing single nucleotide polymorphisms. Two types of synthetic datasets were applied. The first one contained the genomic loci associated with polygenic disease. The second one did not have such loci.

Although several dozen genetic loci have been associated with ischemic stroke, they describe only about 2% of the phenotypic variability in patients, indicating the potential for identifying additional genetic factors. The paper summarizes the results of applying our technology for processing transcriptomic data obtained under conditions of modeling cerebral stroke in rats to search for candidate genes associated with ischemic stroke in humans.

Introduction. Deletions at the 1q23q25 locus cause a distinctive phenotype including proportionate short stature, microcephaly, brachydactyly, dysmorphic facial features, and intellectual disability. Other less commonly reported features include renal, cardiac and genital malformations, craniosynostosis, and single palmar crease.
Objective. To identify and characterize a novel deletion at the 1q24.3q25.3 locus in a proband with growth hormone deficiency and natural anticoagulant deficiency.
Methods. The proband was a 7-year-old girl with proportionate intrauterine growth retardation, congenital heart defects, hyperfibrinogenemia and antithrombin III deficiency. The only case in the family. Differential diagnoses included microchromosomal pathology and acromelic dysplasia. Whole genome sequencing was performed for the mother and proband. The father is categorically against any research.
Results. The proband has a heterozygous deletion at the 1q24.3q25.3 locus, which is about 9.232 Mb. This deletion includes the following genes with an autosomal dominant type of inheritance: LHX4, SERPINC1, XPR1, MYOC, FASLG.
Conclusions. The study identified a deletion of the long arm of chromosome 1. This new mutation is the first identified case of a deletion syndrome at the 1q23q25 deletion locus in Russia and is the cause of short stature, facial dysmorphia, and thrombophilia in the proband. Early detection of this syndrome and proactive intervention may improve quality of life.

Hypomelanosis of Ito is one of cutaneous patterns of pigmentary mosaicism characterized by regions of skin hypo- and hyperpigmentation and associated with mosaic numerical and structural chromosomal abnormalities. A comprehensive cytogenetic and molecular cytogenetic analysis was conducted on cells derived from two tissues of seven patients initially diagnosed with «Hypomelanosis of Ito». In two of these patients, mosaic segmental tetrasomy involving the distal region of the q-arm of chromosome 13 was identified. This chromosomal abnormality is not typically associated with hypomelanosis of Ito but is instead linked to another form of pigmentary mosaicism, known as phylloid hypomelanosis. These findings underscore the importance of employing cytogenetic and molecular cytogenetic techniques as a critical component in the differential diagnosis of various forms of pigmentary mosaicism.

Introduction. Skeletal muscles are one of the most complex tissues for transfection, and therefore the development of approaches to the delivery of genetic constructs for the purposes of gene therapy of hereditary neuromuscular diseases (NMD) is relevant.
Aim: the study of DNA complexes/PEI with anionic peptide coating as vehicles of delivering DNA to cells under physiological conditions, as well as to muscle tissues.
Methods. Physicochemical (size, charge, resistance to polyanions), toxic (resazurin test), and transfection (lacZ and GFP gene expression) triple complexes of DNA and polyethylenimine coated with glutamate-rich polypeptides were studied. C57BL/10J mdx mice were used for in vivo experiments.
Results. It has been demonstrated that the developed DNA/PEI/polypeptide complexes are non-toxic, resistant to relaxation caused by polyanions, and can ensure the delivery of genetic constructs to cells and muscle tissues.
Conclusions. The studied triple complexes demonstrated high efficiency of delivering marker genes to muscle tissue and can later be used to deliver gene constructs for the treatment of NMD.