Breast cancer (BC) occupies the first place in the structure of cancer incidence and mortality from malignant neoplasms among the female population of the Russian Federation. According to the latest statistics, there has been a steady increase in the incidence of breast cancer, which requires a more thorough study of possible measures to prevent its development. One of the modern methods of examination for suspected breast cancer is to carry out a genetic study for mutations that increase the risk of developing breast cancer compared with a group of patients with sporadic breast cancer. So, today a large number of genes are known that are associated with an increased risk of developing breast cancer, these genes include: BRCA1, BRCA2, CHEK2, TP53, STK-11 etc. If one or another mutation is detected in a patient, the risks of developing breast cancer increase, and if the disease has already been realized, then the risks of developing cancer of the contralateral breast. Thus, the cumulative risk of developing breast cancer in carriers of mutations in the BRCA1 gene to 80 years old is 72%, while the risk of developing ovarian cancer is 44% and 40% the risk of developing cancer of the contralateral breast. For carriers of mutations in the BRCA2 gene, the cumulative risk of developing breast cancer is 69%, the risk of developing ovarian cancer is 17% and 26% is the risk of developing cancer of the contralateral breast. Given the significant increase in the risks of developing breast cancer with carriage of a mutation in a particular gene, today, the urgent issue is the introduction of preventive surgery into widespread practice, since it is the implementation of preventive mastectomy that can significantly reduce the risks of developing breast cancer. This literature review presents the most relevant articles affecting this topic.

Ovarian cancer (OC) is one of the most common malignancyof the female reproductive system. High rates of morbidity and mortality from this type of cancer indicate the need for a deeper understanding of the molecular genetic basis of the disease, which in turn will contribute to the development of new approaches to the diagnosis and treatment of OC. Recently, when studying the pathogenesis of malignant neoplasms of the ovaries, a great interest of scientists around the world is directed to studying the role of the immune response and inflammation genes in the development of the OC. At this work presents the results of the study of the role of the polymorphic loci of the genes NFKB1 (rs28362491), IL6 (rs1800795), IL18 (rs1946518) and IL23R (rs7517847, rs10889677) in the pathogenesis of ovarian cancer in women from the Republic of Bashkortostan.The material for the work was the DNA samples of women with an established diagnosis of ovarian cancer (n = 238) and healthy individuals (n = 284). Genotyping of DNA samples was performed using polymerase chain reaction (PCR), followed by analysis of restriction fragment length polymorphism and allele-specific PCR. It has been established that the genetic markers of the risk of developing ovarian cancer for women of Russian ethnicity at premenopausal age are the genotypes rs28362491* ID in the NFKB1 gene and rs1946518 * CA in the IL18 gene. The carrier of the rs1800795 * GG genotypes in the IL6 gene and rs10889677 * CС in the IL23R gene for post-menopausal women of Tatar ethnicity is a protective factor. For Tatars with the rs10889677 * CA genotype in the IL23R postmenopausal gene, on the contrary, an increased risk of developing the disease was shown. Markers of a reduced risk of developing ovarian cancer in Russians can also include the rs1946518 * AA genotype in the IL18 gene, which was noted as a protective factor for women in both pre- and postmenopausal women, as well as in patients with this oncopathology with initial and advanced stages of the disease. A comparative analysis of the frequency distribution of alleles and genotypes of the polymorphic variant rs7517847 in the IL23R gene among patients with OC and healthy donors did not reveal statistically significant differences between the studied groups.

A study was made of interferon-induced transmembrane protein 5 gene (IFITM5) in 99 patients with osteogenesis imperfecta (OI) from 86 unrelated families and a search for pathogenic gene variants involved in the formation of the disease phenotype. OI is a clinically and genetically heterogeneous hereditary disease of the connective tissue, the main clinical manifestation of which is multiple fractures, starting from the natal period of life, often leading to disability from childhood. The main clinical signs of OI include blue sclera, hearing loss, anomaly of dentin, increased fragility of bones, impaired growth and posture, with the development of characteristic disabling bone deformities and associated problems, including respiratory, neurological, cardiac, and renal disorders. OI occurs in both men and women. The degree of genetic heterogeneity of the disease has not yet been determined. To date, 20 genes are known to be involved in the pathogenesis of OI, and researchers from different countries continue to search for new genes. In the last decade, it has become known that autosomal recessive, autosomal dominant and X-linked mutations in a wide range of genes encoding proteins that are involved in the synthesis of type I collagen, its processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells cause OI. Mutations in the IFITM5 gene, also called BRIL (bone-restricted IFITM-like protein), involved in the formation of osteoblasts, lead to the development of OI type V. Up to 5% of patients have OI type V, which is characterized by the formation of a hyperplastic callus after fractures, calcification of the interosseous membrane of the forearm, and a mesh lamellar pattern observed during histological examination of the bone. In 2012, a heterozygous mutation (c.-14C> T) in the 5’-untranslated region (UTR) of the IFITM5 gene was identified as the main cause of OI type V. In the present work, the IFITM5 gene was analyzed and the de novo c.-14C> T mutation was identified in one patient with OI who was subsequently diagnosed with type V of the disease. Three known polymorphic variants were also identified: rs57285449; c.80G> C (p.Gly27Ala) and rs2293745; c.187-45C> T and rs755971385 c.279G> A (p.Thr93 =) and one previously undescribed variant: c.128G> A (p.Ser43Asn) AGC> AAC (S / D), which were not pathogenic. The article focuses on the features of the clinical manifestations of OI type V, and it is recommended to determine the c.-14C> T mutation in the IFITM5 gene if this form of the disease is suspected.

The study aim was to assess the frequency of heterozygous carriage of mutations in the CFTR, PAH, GALT, and GJB2 genes among healthy individuals. Materials and methods. The study involved 1000 blood donors living in Moscow and 1168 employees of the FSBI Research center for obstetrics gynecology and perinatology MOH Russia, living in Moscow and the Moscow region. All participants in the study did not have clinical manifestations of hereditary diseases. Molecular genetic studies of the samples were carried out by analyzing the most frequent mutations in the CFTR, PAH, GALT and GJB2 genes, using real-time PCR technology Results. 46 carriers of mutations in the CFTR gene, 63 carriers of mutations in the PAH gene, 12 carriers of mutations in the GALT ge ne and 74 carriers of mutations in the GJB2 gene were identified. In addition, in 3 cases, a combined carriage of mutations was found: CFTR: F508del + GALT: Q188R; CFTR: dele2.3 (21kb) + GJB2: 35delG; GJB2: 35delG + GALT: Q188R. Conclusion. The data obtained indicate a fairly high level of carriage of the studied diseases. Thus, there are prerequisites and opportunities for diagnosing the carriage of the most common autosomal recessive diseases in the population. Such studies can be an effective tool for the prevention of hereditary pathologies and reduce the incidence of diseases.

The most common cause of non-syndromic hearing loss in various populations of the world is the mutations in the GJB2 gene. Previously it was shown that the pathogenic contribution of the GJB2-mutations among patients with congenital hearing loss in Yakutia was 49%. The aim of this work was to investigate the molecular genetic basis of hearing loss among GJB2-negative patients. The study included 238 (228 unrelated) GJB2-negative patients, among them we found one family with five affected individuals with juvenile hearing loss of unknown etiology (the disease onset varied from 0 to 8 years). Using a whole exome sequencing (WES), performed in one of affected family members, a novel homozygous c.1121G>A (6p21.1, OMIM 607293) substitution in exon 6 of the CLIC5 gene was detected. This substitution leads to the formation of a premature stop codon at the 374 amino acid position (p.Trp374*) which terminates the synthesis of the polypeptide chain of the CLIC5 protein (NP_001107558.1). To date, only one homozygous mutation c.96T>A (p.Cys32*) was known in human gene CLIC5 which was found in one inbred Turkish family with progressive autosomal recessive deafness, type 103 (DFNB103). In our study, a homozygous variant c.1121G>A (p.Trp374*) was detected in 26 out of 238 GJB2-negative patients in Yakutia (10.9%). Most of homozygous for c.1121G>A patients (19 out of 26) reported about late onset of their hearing loss occurred in postlingual period (averaged 9.7±0.6 years). Audiological examination of 13 out of 26 patients revealed predominantly symmetric sensorineural progressive hearing loss of varying severity (from mild to profound hearing loss). The average prevalence of DFNB103 caused by the homozygous variant c.1121G>A (p.Trp374*) in Yakutia was 0.27±0.053 per 10000 with a maximum accumulation in Eveno-Bytantaysky district (31.39±10.46 per 10000) which referred to the Arctic group of districts where the majority of the population is represented by Evens (53%). This is the first case of the identification of the orphan disease with its accumulation in Arctic part of Russia. In general, the homozygous variant c.1121G>A (p.Trp374*) of the CLIC5 gene can be regarded as causative to DFNB103 with a high contribution to the etiology of hearing impairments in the population of Yakutia.