The effectiveness of medical care for children with rare hereditary diseases in a specialized genetic clinic was analyzed. About half of the hospitalized patients (and their relatives) needed genetic research to establish or confirm the diagnosis, clarify the form of the disease, and provide medical and genetic counseling. About 20% of the examined children required additional genetic testing or repeated bioinformatic interpretation of the data.

The paper describes the principles of creating a computer consultative decision support system for the diagnosis of hereditary diseases at the pre-laboratory stage. The prototype is implemented on the example of the clinical manifestations of lysosomal storage diseases. The system is based on literary data, which are accompanied by expert assessments. The developed intellectual system forms a limited differential diagnostic row of hypotheses. It provides assistance to the geneticist in differential diagnosis both in the presence of a preliminary diagnosis and in the absence of assumptions about the nosology of the disease.

The concept of creating a centralized platform for clinical and laboratory genetics is presented, as well as an analysis of competitive products that provide various functions.

A pilot study was conducted to assess the existing problems of the prescriptive approach of Russian geneticists in genetic counseling

In this paper we considered two types of ethical and legal problems regarding patient autonomy in perspective of the communicative features of the medical genetics. Also, this paper shows the role of the primary consultation in solution of this problems.

Summary data on the activities of the medical and genetic consultation of the Astrakhan region for the period 2017-2019 are presented.

RASopathies - group of inherited diseases, caused by mutations in genes, encoding components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. We identified 28 patients with inherited diseases from RASopathies: 61% - with Noonan syndrome, 14 % - with Cardiofaciocutaneous syndrome, 14% - with Costello syndrome - 11% - Noonan syndrome-like with loose anagen hair. Mutation c.770C>T, p.S257L in RAF1gene is most common in hypertrophic cardiomyopathy patients with Noonan syndrome. All patients with Noonan syndrome-like with loose anagen hair have mutation c.4A>G , p.S2G in SHOC2 gene.

A retrospective clinical and genealogical analysis of 20 patients with a diagnosis of tuberous sclerosis was performed. According to the results of molecular genetics diagnostics, 4 different pathogenic variants of the nucleotide sequence in the TSC1, TSC2 genes were identified in 3 unrelated Yakut and 1 Russian family.

Studies of hereditary pathology of the eye against the background of broad genetic heterogeneity and pronounced clinical polymorphism are difficult because of the complexity of determining the focus of primary damage - often diseases of the anterior segment of the eye are triggers for damage to the posterior segment (retina, choroid, optic nerve). The presented report describes the structure of the spectrum of PAX6-associated pathology of the eye in a clinically polymorphic sample, taking into account the level of damage to the eyeball.

Aniridia (OMIM 106210) is an autosomal dominant congenital disorder caused by heterozygous PAX6 intragenic mutations or chromosome 11p13 rearrangements. Molecular genetic study aimed to determine PAX6 damage spectrum peculiarities in Russian cohort. 152 unrelated families with congenital aniridia (184 patients) underwent ophthalmic examination and DNA testing. 17 patients from 12 unrelated families (4 familial and 8 sporadic probands) shared likely the same 11p13 0.3-1.5 Mb deletion affecting PAX6 downstream regulatory regions. The frequency of these deletions, 8% (12/152), was higher than PAX6 hotspot c.718C>T rate (8/152, 6%). A high rate of the deletions suggests a common underlying mechanism of its formation and points to 11p13 genomic region instability.

Inherited ophthalmological pathology is a heterogeneous group of diseases that manifests itself either as an isolated eye disorder or as a symptom of hereditary syndromes (chromosomal or monogenic). Thus, diagnostic search in some cases of ophthalmologic pathology can be laborious and expensive. The most difficult situation may arise when antenatal diagnosis is required during the ongoing pregnancy. In the present report the necessity of timely application of high-throughput sequencing methods in ophthalmogenetic practice is considered. Polymorphism of inherited ophthalmologic pathology may seriously hinder making an accurate diagnosis and make it time consuming and expensive. In complex cases, HTS appears to be a method of choice, and it can significantly speed up diagnosis confirmation of and genetic risk assessment.

Reduced vision acuity in congenital aniridia is associated with a defect in the iris and a complex of changes of varying degrees of severity in other eye structures (cornea, optic nerve, retina, etc.). Prediction of changes in refraction is a complex problem, since there are wide variations in the state of the structures and functions of the eye from birth and their dynamics with age, as well as variations due to both genetic factors and the adequacy of treatment and prophylactic measures as well as patient’s adherence to therapy. The article describes the changes in refraction in children aged from 0 to 7 years old with PAX6-associated congenital aniridia.

We present the results of molecular genetic studies of the congenital cataract (CTRCT18, MIM 610019) common in the Sakha Republic of Russia.

Studying the mutation spectrum and improvement of molecular verification of the Usher syndrome (USH) are of particular relevance as gene therapy emerges. Among 46 patients with signs of Usher syndrome we identified mutations in 40 (85%) patients, establishing a diagnosis of USH1 and USH2 for 26% and 57% of the probands of the initial sample, respectively. Patients with USH1 showed mutations in the MYO7A (73%), CDH23 (7%), PCDH15 (7%), and USH1C (13%) genes. MYO7A p.Q18* mutation showed the highest frequency. We have identified 6 new mutations in the MYO7A gene, and 2 in the PCDH15 gene. In USH2 patients, 21 USH2A gene mutations were identified, 5 of which are novel. The USH2A mutation p.W3955* was most frequent. Two patients showed mutations in the non-syndromic retinitis pigmentosa genes RHO and RPGR, which made it possible to clarify the clinical diagnosis.

The aim of this study was to characterize phenotype-genotype correlations in patients with ABCA4-associated IRDs. By NGS, we have identified the widespread “mild” ABCA4 mutation p.G1961E in 20 of 54 IRD patients with at least one mutation in the ABCA4 gene. In 8 patients, p.G1961E was in combination with a complex missense mutation p. [L541P; A1038V], in six - in combination with other missense mutations (p.N1805D; p.R1640W; p. P1088T; p.L541P; p.P1380L; p.R1640Q). In 81% of our patients with a disease course of 9 years or more, the p.G1961E mutation is associated with mild disease, even in the presence of a second severe mutation, and is a predictor of a milder phenotype, in accordance with the basic model of phenotype-genotype correlations in ABCA4-associated diseases.

Inherited retinal disease (IRD) is a class of ophthalmic disorders in which can be classified into diseases of primarily of rod system and with primarily of cone system, which include macular dystrophies. In the presented report the structure of spectrum of IRD in clinically polymorphic is presented on the base of clinical, molecular-genetics and instrumental (OCТ, autofluorescencе, eletroretinography).

So far, the Online Mendelian Inheritance in Man (OMIM) database describes more than 6613 diseases and phenotypes, 4241 have a proven genetic basis, 45% of which are combined with ophthalmological manifestations. The article provides a number of clinical examples of patients with ophthalmological manifestations of various genetic diseases (alcaptonuria, Stadgart ‘s disease, microcephaly syndrome with or without choriretinopathy; Astrocytic gamartoma) to demonstrate effective clinical-diagnostic screening of genetic pathology in patients.

In the past decade, a genome-wide search for glaucoma associations has identified the associated polymorphic loci with glaucoma. Goal: replicative studies of associations of significant polymorphic loci rs7865618 and rs2157719 of the CDKN2B-AS1 gene with the development of primary open-angle glaucoma in women from the Central Black Earth Region of the Russian Federation. The object of the study was a sample of 290 patients with glaucoma, and 220 people in the control group. It was found that in patients with female glaucoma the frequency of the AA genotype of the polymorphic locus rs7865618 of the GDKN2B-AS1 gene was 34.98%, AG - 46.64%, GG - 13.37%, minor allele A - 41.70%. In women of the control group, the following frequencies of the rs7865618 polymorphic locus were determined: AA - 28.30%, AG - 51.42%, GG - 20.28%, minor allele A - 45.99%, respectively. For rs2157719 of the GDKN2B-AS1 gene among glaucoma patients, the frequency of the AA genotype was 39.01%, AG - 48.40%, GG - 18.72%, the minor G allele was 42.49%, and in the women in the control group, AA - 32.88%, AG - 48.40%, GG - 18.72%, minor allele G - 42.49%, respectively. Conclusions. Polymorphisms rs7865618 and rs2157719 of the GDKN2B-AS1 gene are not associated with primary open-angle glaucoma in women of the Central Region of the Russian Federation.

Primary open-angle glaucoma (POAG) is a chronic eye disease accompanied by an increase in intraocular pressure and specific changes in the visual field. Male gender is a risk factor for glaucoma. The aim of the study is research the role of three-locus models with the participation of 8 polymorphic loci of the matrix metalloproteinases genes (rs679620 MMP3, rs1799750 MMP1, rs2250889, rs3918249, rs17576, rs3918889 and rs17577 MMP9) in the POAG formation among men. We have identified 7 three-locus models of SNP × SNP interactions that determine susceptibility to the development of POAG in men.

The effectiveness of DNA analysis for diagnostics of genetic skeletal disorders (GSD) based on the investigation of the data of 270 Russian patients was evaluated. The usage of various molecular genetic methods allows to clarify the diagnosis in 74% of patients with clinical and radiological signs of systemic skeletal disorders. The incidence of 8 most common groups of NSD was calculated. It has been shown that the most commonly diagnosed conditions included FGFR3-relared chondrodysplasias, collagenopathies and diseases caused by impaired sulfate metabolism, which account for 67.5% of all diagnosed NSD.

Here, we describe a case of a 6-year-old Yakut girl who presented with clinical signs of SOPH syndrome, acute liver failure (ALF) and bone fragility by the type of osteogenesis imperfecta. Targeted panel sequencing for 494 genes of connective tissue diseases of the patient revealed that he carried novel compound heterozygous missense mutation in NBAS, c.2535G>T (p.Trp845Cys), с.5741G>A (p.Arg1914His).

The results of a molecular genetic study of patients with a hypermobile type of Ehlers-Danlos syndrome (hEDS) are presented. A possible algorithm for verifying hEDS and other inherited disorders of connective tissue with unspecified etiology is proposed.

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous hereditary disease of the connective tissue, which is based on genetic changes leading to a violation of the structure of bone tissue. 21 genes are involved in the pathogenesis of OI have been identified, but the degree of genetic heterogeneity of the disease has not yet been clarified. The aim of the study is to search for the molecular cause of OI and determine the type of inheritance and the clinical form of the disease based on the analysis of clinical genetic correlations.

Here we present molecular genetic studies of Yakut patients with hereditary multiple exostoses (HME), which caused by a rare mutation in the EXT2 gene. A total of 65 patients with clinical diagnosis of HME and their relatives from 30 unrelated families were examined. For molecular genetic analysis, massive parallel sequencing (MPS) and direct Sanger sequencing were used. In 16 patients from 4 families with a clinical diagnosis of HME, a rare heterozygous nonsense mutation c.751C> T was detected in exon 5 of the EXT2.

Short-rib thoracic dysplasia (SRTD) is an autosomal recessive disorder characterized by a constricted thoracic cage, short-ribs, shortened tubular bones, polydactyly is variably present. The visceral malformation can include anomalies brain, heart, kidneys, liver, pancreas. We present a case report of prenatally diagnosed Short-rib thoracic dysplasia (SRTD) syndrome.

We examined 116 postmenopausal women. An uneven distribution of the rs1801197 polymorphism genotypes of the CALCR gene was found in the groups of healthy women, patients with osteoporosis and osteopenia (p = 0.036). Among women with osteoporosis and osteopenia, compared with healthy individuals, the C allele is significantly more often recorded (p <0.001).

Osteoporosis is one of the most common multifactorial diseases, which is characterized by a high risk of fractures and microarchitectural disorders of bone tissue. The study of genetic and epigenetic factors of this disease and their contribution to pathogenesis is relevant. We found the significance of the polymorphic variants rs11540149, rs6854081, rs10098470, rs10793442, rs1054204, rs3134069, rs3102734 and rs7844539 in increasing the risk of fractures and forming a low level of bone mineral density.

Osteoarthritis (OA) is a common multifactorial joint disease. Undifferentiated connective tissue dysplasia (uCTD) is a genetically determined lesion of the connective tissue structures, including joints, and it can be one of the factors, predisposing to development of OA. Solving the problem of comorbidity OA and uCTD signs will contribute to the early diagnosis and preventive of OA.

Collagen fibers play a significant role in the formation of the ligamentous apparatus of the pelvic floor. However, previous studies do not give an exact answer about the role of polymorphic variants of collagen genes on pelvic floor dysfunction. The aim of this study was to determine the association of single nucleotide polymorphisms rs1800012 of the COL1A1 gene, rs1800255 and rs1801184 of the COL3A1 gene, rs2236479 of the COL18A1 gene and their combinations with pelvic organ prolapse (POP) and stress urinary incontinence (SUI). The study group consisted of 150 patients with POP and/or SUI. The control group included 100 patients without pelvic dysfunction. Patients were comparable in age and external risk factors.All patients received a buccal epithelium for analysis. Sequencing was carried out by the Sanger method. Association between the rs1800012 polymorphisms of the COL1A1 gene, rs1800255 and rs1801184 of the COL3A1 gene, rs2236479 of the COL18A1 gene and pelvic dysfunction were not detected.

Clinical case of patients from the same family with a rare genetic disease - Allan-Herndon-Dudley syndrome - is presented. Family history, similar clinical symptoms, genetic analysis are important for the diagnosis of this genetic syndrome.

Нereditary syndromes of multiple congenital malformations (MCM) are a large group of chromosomal and monogenic diseases, currently reaching more than 3 thousand forms. Diagnosis and verification of MCM syndromes is often difficult due to the variety of forms, inter-family and intra-family clinical polymorphism, and in sporadic cases, the most reliable will be with a full set of phenotypic features. In addition, differential diagnosis can also be difficult due to the similarity of phenotypic features in different syndromes. In such cases, the use of high-performance DNA sequencing methods can solve the problem of clarifying the diagnosis and resolving the issue of whether prenatal diagnosis of the disease in the fetus can be carried out in the family during subsequent pregnancy. As a result, NGS diagnosed a rare variant of Joubert syndrome, without molecular genetic verification, diagnosis would be difficult.

Andersen-Tawil syndrome is a rare autosomal dominant disease characterized by periodic paralysis, cardiac dysrhythmias, distinct facial and skeletal characteristics, that may be variably present in the affected members. In the article there is a clinical case with atypical presentations. The correct diagnosis has been done due to results of DNA sequencing.

We present a sporadic case of Smith-Lemli-Opitz syndrome (SLOS) in the fetus of the second trimester. The ultrasound (US) signs were similar to the syndrome of short ribs-polydactyly (SCRP). The diagnosis was established by molecular genetic testing. The atypical manifestations of SLOS are discussed and compared with literature data.

Chronic pancreatitis (CP) is an urgent problem of modern medicine. If CP manifests in childhood, the course of the disease is particularly severe and often requires surgical treatment. In Russia there are few investigations of the genetic causes of pancreatitis. There is even less data on the influence of genetic factors on the pancreatitis development in children. In this study we performed genotyping of 25 CP patients with a clinical manifestation of the disease at the age under 20 years old. Genetic analysis was carried out by Next Generation Sequencing (NGS). All coding regions of the SPINK1 and PRSS1 genes were analyzed. Mutations of the mentioned genes were found in 11 patients (44%). The spectrum of mutations and the clinical course of CP in Russian individuals younger than 20 years old have been established. The identification of the molecular genetic cause of CP helps to predict the severity of the disease and to prevent the disease in the relatives of the patient.

We performed the comparative analysis of the genetic structure of a predisposition to the progression of liver fibrosis in HCV-related infections and alcoholic liver disease. Genotype СС rs708272 of CETP gene was associated with cirrhosis in HCV-infected patients (OR=4,08[95%CI:1,69-10,03]; р=0,001). Genotype CG rs12054703 of NUP155 gene was associated with alcoholic liver cirrhosis (OR=1,86[95%CI:1,11-3,13]; р=0,016). Genotype CG rs7590760 of DNMT3A gene had protective effect on the alcoholic liver cirrhosis (OR=0,43[95%CI:0,24-0,78]; р=0,004). The genetic structure of a predisposition to liver cirrhosis is different for chronic hepatitis C virus infection and alcohol-induced liver injury.

DNA samples extracted from the blood of 99 people aged 20 to 80 years were used as the material for our research. Among these people 47 were infected with HBV and 52 were not. The reseach found that the allele A of the rs1800450 polymorphism of the MBL2 gene is associated with a high risk of hepatitis B, and the presence of the GG genotype reduces this risk; interaction of polymorphic variants of the STAT3 gene with a GG genotype of the MBL2 gene reduces the risk of hepatitis B.

Associations of eQTL SNPs of the TLR4, CAT, IL10, ADRB2, CST3, ICAM1, IRF6, NFKB1, PNP, SELL, SPP1, SMC2, SERPINA1, IL2RB, HSPA4, FOS, NT5C2, BHLHE40 genes with bronchial asthma, arterial hypertension and the comorbidity of these diseases were studied. As a results association of alleles, genotypes, and haplotypes formed by individual SNPs of TLR4, CAT, ANG, and RNASE4 genes with comorbidity of asthma and hypertension have been established which differ from SNPs associated with “isolated” asthma and arterial hypertension.

In the present study, we established associations of the genes TNF (rs1800629); TNFB (rs2239704) and TNFRSF1B (rs652625) with the development of bronchial asthma and tuberculosis. Differences in the TNF gene transcription pattern depending on the genotype and the effect of stimulators of microbial/non-microbial origin (LPS, IFN-γ) suggest the functional significance of the single nucleotide substitution G>A (rs1800629) of the TNF gene.

Asthma is one of the most common severe and disabling chronic diseases. It has been shown that up to 50-60% of sensitivity to asthma therapy is due to genetic variability. The study of polymorphisms of genes involved in the metabolism of beta-2-agonists (CRHR2, ADCY9, THRB, SPATS2L) and histamine (AOC1, HRH4) in asthma patients and individuals of the control group of different ethnicities were carried out.

The search for genetic and epigenetic markers of the risk asthma and sensitivity to glucocorticosteroid therapy (GCs) in Russians, Tatars and Bashkirs was performed. It was established that polymorphic variants of genes involved in the metabolism of GCs (NR3C1, CRHR1, GLCCI1, TBXT, FBXL7) affect the features of the development and course of asthma. An analysis of the methylation status of the glucocorticoid-induced transcript 1 GLCCI1 gene revealed an increased level of methylation of the promoter region of the GLCCI1 gene in asthma patients.

The research of genetic features of dystropic diseases (including asthma and tuberculosis) that determine the formation of mutually exclusive phenotypes at the clinical level is important for a better understanding of their pathogenesis. The aim of this study was to assess the significance of the genetic polymorphism of the NBN gene in the formation of a predisposition to asthma and tuberculosis. The variability of rs1805800 and rs709816 of the NBN gene in the samples of patients with bronchial asthma (BA), tuberculosis (TB) and the population sample of Tomsk (PV) was studied, the total sample was 683 people. The different-directional change of frequencies of alleles, genotypes, combinations of genotypes by rs1805800 and rs709816 of the NBN gene between groups of patients with BA and TB compared to the population sample is shown. For the development of BA, the genotype CT rs1805800 is risky (OR=1.66, χ2=5.41, p=0.02); And the SS genotype is a protective (OR=0.57, χ2=5.57, p=0.018) effect. Statistically significant differences between BA and TB groups are also revealed by the frequencies of combinations of the genotypes rs1805800/rs709816 in the NBN gene (χ2=12.88; p=0,045).

Chronic obstructive pulmonary disease (COPD) is a multifactorial heterogeneous chronic inflammatory disease of the respiratory system predominantly affecting the lower respiratory pathways and the lung parenchyma. One of the reason for difficulties in identifying of COPD markers is phenotypic heterogeneity. The goal of the study is the identification of new molecular markers of pathogenetic changes associated with phenotypic heterogeneity of COPD based on the analysis of the expression profile of genes involved in the development of the immune response in peripheral blood mononuclear cells and analysis of the association of polymorphic variants of new candidate genes with COPD. Methods: to identify differential gene expression in COPD we performed expression profiling of 84 cytokines and chemokines genes in peripheral blood samples from COPD (N=10 with frequent exacerbation phenotype, N=10 rare exacerbation phenotype) and N=10 smoking controls. RNA was isolated from PBMCs, and gene expression was assessed using RT2 Profiler PCR Arrays «Human Cytokines & Chemokines PCR Array»» (Qiagen, Valencia, CA, USA). 56 SNPs of JAK / STAT-, NFKB1-signaling pathway and inflammatory response molecules genes were genotyped by the real-time polymerase chain reaction (TaqMan assays) in a case-control study (601 COPD patients and 617 controls). Results. Significant changes were revealed in the expression profile of several genes in “frequent exacerbator» COPD phenotype. The results indicate a down-regulation of inflammatory molecules in “frequent exacerbator» COPD phenotype. For the first time, we indicated the contribution of JAK1, JAK3, STAT3, ICAM1, PECAM1, SAA1, NFKB1, IL17A, CCR2, CCR6, CCL8, CRP, CX3CL1, CXCR2, CXCR1, TNFRSF1A, IL20, IL19 genes polymorphisms to COPD. Specific genetic markers of “frequent exacerbator” COPD phenotype have been identified, which are modifiers of COPD progression, including polymorphic loci of the CXCR2, TNFRSF1B, CCR6, TNF, IL1B, IL10, JAK3, PECAM1 genes. A significant genotype-dependent variation of lung function parameters was observed for CXCR2, JAK1, NFKB1, PECAM1, ICAM1, STAT1, LTA, CD14, CXCL12, CCL20, ADIPOR1 and CX3CR1 genes. The relationship of IL17A, JAK1, JAK3, NFKB1, CCL5, CCL11, CCL17, CXCL8, TNFRSF1A, CX3CL1, CCL8, CCR6, CXCR2, IL19, IL20 genes with smoking pack-years was found.

We examined 21 patients with clinical manifestations of ichthyosis vulgaris. Most often, they had the 2282del4 mutation in the FLG gene both in homozygous (in 6 patients) and heterozygous states.

Atopic dermatitis (AD) is an inherited inflammatory disease of skin, multifactor or monogenic nature, characterized by itching, chronic recurrent current and age-specific features of localisation and morphology of lesion centers. The proportion of the disease in the structure of skin diseases is currently between 10 and 30%. When the process acquires a persistent course with an unparalleled effect from the performed therapy and exacerbations of the process up to 3-4 per year with increase of their duration, it becomes sluggish (torpedo) [1, 3]. The torpedo course of AD leads the patient to a decrease in the quality of life due to physical discomfort and emotional disadaptation. Approaches to treatment in theory depend on the mechanism of disease development.