Objective: to study the influence of the genetic structure on the values of the load and diversity of isolated hereditary diseases of the visual organ (HPOV) and included in the hereditary syndromes and diseases in the populations of the Russian Federation.

Methods: the analyzed sample is represented by 17 populations (12 ethnic groups from 14 regions of the European part of the Russian Federation), the number of the surveyed population is about 4 million. People: Russians from 6 regions of the Russian Federation (Kirov, Kostroma, Tver, Bryansk, Rostov regions and Krasnodar Krai), five ethnic groups from the Volga-Ural region (Tatars from Tatarstan, Bashkirs from Bashkortostan, Mari from Mari El, Chuvash from Chuvashia, Udmurts from Udmurtia) and six peoples of the North Caucasus (Ossetians from North Ossetia, Adygeans from Adygea, Abazines, Circassians, Nogais, and Karachays from Karachay-Cherkessia). Data on random inbreeding (Fst) and migration index (MI), accumulation coefficient (AC) in the same surveyed populations were used to assess the role of drift in the genetic differentiation of populations according to the load and diversity of HDOV.

Results: The clearest dependence and higher correlation coefficients were obtained by analyzing the relationship between the total values of the load of the HPOV) (isolated hereditary ophthalmopathology and included in hereditary syndromes and diseases) from the values of random inbreeding FST in the populations of the Russian Federation: for the total HPOV with the AD type of inheritance, the correlation coefficient was 0.616±0.204, 0.687±0.194 for AR and 0.581±0.218 for X-linked. The analysis of the relationship between MI and the burden of the HPOVshowed low correlation coefficients for AR and X-linked diseases in all the groups under consideration, and significant for the group with AD type of inheritance in all the groups under consideration: isolated (-0.612±0.211), syndromic (-0.497±0.232) and total (-0.577±0.218). The analysis of the regression relationship between the AC for populations and the values of FST and MI showed high and significant correlation coefficients (r= 0.842±0.163 and r= – 0.672±0.262, respectively).

Conclusions. Asaresult of the analysis of the dependence of the burden and the diversity of the HPOV on the parameters of the genetic structure, it is shown that the main factors in the dynamics of the gene pool, which most determines the differentiation of Russian populations by burden and by the diversity of the HPOV, as well as causing the local accumulation of individual hereditary diseases with damage to the organ of vision in the examined populations, are gene drift, subdivision populations and migration characteristics.

Aneuploidy is a numerical chromosome abnormality in a diploid set in a cell. The most common aneuploidies observed in case of live birth are aneuploidies on chromosomes 13, 18, 21, X, and Y. At the present moment, it is possible to use a fast, reliable, and cheap method of quantitative fluorescent polymerase chain reaction (QF-PCR) for diagnosing frequent aneuploidies. The analysis of 1192 prenatal samples and 195 postnatal samples using this method detected various chromosomal abnormalities in 15% of cases. The most frequently detected aneuploidy was a trisomy 21 - 9.7%. The trisomy 18 rate was 2.0%, trisomy 13 - 0.3%. Among the anomalies of the sex chromosomes, Klinefelter syndrome was found in 1.1% and Turner syndrome in 0.8% of cases. There was a decrease in the proportion of aneuploidies accompanied by severe malformations in postnatal samples. The high level of the STR markers heterozygosity used in the study made it possible to obtain results in all samples for analyzed chromosomes. It is most preferable to use the QF-PCR method for prenatal examination of patients with suspected frequent fetal aneuploidies during late pregnancy or to confirm chromosomal abnormalities in case of aneuploidy detection by noninvasive prenatal test and for postnatal diagnosis of unbalanced chromosomal abnormalities.

Mutations in the glucocerebrosidase (GBA) gene are the most common risk factor for developing Parkinson’s disease (PD). In the homozygous, as well as in the compound heterozygous state, mutations in this gene lead to a decrease in the enzymatic activity of glucocerebrosidase (GC), an increase in the level of its substrate hexosylsphingosine (HexSph) both in brain cells and peripheral blood, and the development of a hereditary disease belonging to the class lysosomal storage disease Gaucher disease (GD). The literature is increasingly discussing the use of GC pharmacological chaperones (PC) for the treatment of both GBA-PD and neuropathic forms of GD. The aim of the study was to identify among a wide range of known drugs potential PC of the most common mutant form of N370S GC, which are not competitive inhibitors of the enzyme.

The studies were carried out by molecular modeling methods in two stages, using the atomic model of the N370S GC mutant form that we constructed earlier. First, a virtual screening of 2089 chemical compounds approved for use in clinical practice was carried out, asaresult of which 26 compounds were selected that have the smallest value of the calculated evaluation function characterizing protein affinity. These drugs belonged to different pharmacological groups, of which 6 were selected for further study, which can be taken in clinical practice for a long time. The stability of six complexes of GC with selected chemical compounds was checked by the method of molecular dynamics with explicit allowance for the aqueous environment. The free energy of binding of four compounds (flavin mononucleotide, rebamipide, benfotiamine, olopatadine) calculated by the MMGBSA method is less than -35 kcal/mol. Thehighest probability of penetration through the blood-brain barrier, predicted by the ADMET web server, for the Olopatadine (at 17%) and Benfotiamine (at 12%).

Thus, as a result of the study, potential pharmacological chaperones of GC were selected from an expanded database of approved drugs for use, the ability of which to increase its enzymatic activity, as well as to reduce the level of the HexSph substrate requires further study.

Background. Familial exudative vitreoretinopathy (FEVR) is a rare hereditary genetically heterogeneous disease characterized by impaired retinal angiogenesis and variable clinical manifestations. The FZD4 gene is the most studied of those associated with FEVR. Molecular genetic examination of a large cohort of patients with FEVR in the Russian Federation was not carried out.

Objective: to study the spectrum of variants of the nucleotide sequence of genes in patients with FEVR in the Russian Federation, to identify clinical and genetic correlations.

Methods. 58 patients (31 girls, 27 boys) with FEVR aged from 3 weeks to 17 years were examined in an interdisciplinary manner at the Helmholtz National Research Centre of Eye disease and the Research Centre for Medical Genetics. All patients underwent an in-depth ophthalmological examination. The molecular genetic examination was carried out by direct Sanger sequencing and high-throughput sequencing methods.

Results. Variants of the nucleotide sequence of the FZD4 gene were found in 10 patients (17.2%) from 9 unrelated families, of which 3 were identified for the first time. Single-nucleotide deletions and substitutions were identified with the same frequency. The features of patients with identified variants of the nucleotide sequence of the FZD4 gene are early manifestation, asymmetric lesion, progressive course and autosomal dominant inheritance.

Biotinidase deficiency is a hereditary disease associated with mutations in the gene encoding biotinidase and accompanied by neurological (epileptic seizures, muscle weakness, psychomotor retardation) and metabolic (metabolic acidosis, increased excretion of organic acids in the urine) defects. The diagnosis is made based on clinical and laboratory findings.

Timely administration of high doses of biotin compensates for its deficiency, restores the function of biotin-dependent carboxylases, and alleviates clinical symptoms of the disease. 

This article presents the results of the therapeutic application of a specialized dietary supplement «Biotin Vitamin Complex» in patients with biotinidase deficiency.

Pathogenic variants of the SLC26A4 gene are associated with both autosomal recessive deafness type 4 (DFNB4, OMIM #600791) and Pendred syndrome (PS, OMIM #274600). In this work, we searched for causative variants of the SLC26A4 gene and its genetic background (CEVA haplotype) in six patients in Buryatia with hearing impairments and an enlarged vestibular aqueduct (EVA), which in some cases was combined with cystic cochlear anomalies (IP-1 and IP-2) and with impaired thyroid function. The study included clinical and audiological analyses of hearing thresholds, computed tomography of the temporal bones, analysis of hormones of the hypothalamic– pituitary–thyroid axis (TSH, free T3 and free T4), direct Sanger sequencing of the coding regions of the SLC26A4 gene (21 exons) and genotyping of 12 SNPs markers of the CEVA haplotype. In general, among the studied patients, the proportion of SLC26A4 biallelic (M2) and monoallelic cases in combination with the CEVA haplotype in trans-position (M1+CEVA) was 83.3% (5 of 6 cases). At the same time, in Buryat patients, the proportion of cases with M2 was 100% (3 out of 3 cases), while in Russian patients, the proportion of cases with M2 and M1 + CEVA was 66.6% (2 out of 3 cases). The high contribution of the SLC26A4 gene in Buryat patients may be associated with the prevalence of the major variants of this gene c.919-2A>G (IVS7-2A>G) and c.2027T>A p.(Leu676Gln) common for regions of Siberia and Eastern Asia. Identification of the CEVA haplotype in trans-position in one Russian patient with a monoallelic variant of the SLC26A4 gene (M1+CEVA) indicates the relevance of further assessment of the diagnostic significance of the CEVA haplotype in cohorts of Russian patients with hearing impairments.