Whole-genome and whole-exome sequencing have universally recognized clinical importance for the diagnosis of orphan diseases. Due to the development of sequencing technology and the subsequent reduction in diagnostic costs, these methods are increasingly used not only for clinical purposes, but also as a screening tool in healthy individuals. The study for suspected genetic disease in the family or testing a healthy person «optional» can be revealed «incidental findings» with different clinical significance. However, a number of professional guidelines recommend a systematic search for clinically significant secondary results - the so-called opportunistic screening. Accordingly, the ethical problems of opportunistic screening actively discussed, particularly in the context of the proportionality of the benefits and risks for the tested person, informed consent and the protection of autonomy and justice. Ethical problems of genetic counseling in modern economic and technical aspects in the Russian Federation have been little studied. This review article describes the problems mentioned, provides international experience and recommendations for solving the aforementioned problems.

Background: Developmental delay (DD) and intellectual disability (ID) are frequent symptoms in patients consulted by a geneticist. Purpose of the research: evaluation of the structure and variety of nosological forms of DD and ID and their dynamics among patients consulted by geneticists of the counseling unit and research and counseling department of the Research Centre for Medical Genetics in 2006, 2007, 2016 and 2017. Materials and methods: The present work was performed on the material taken from the medical genetic cards of patients of the Research Centre for Medical Genetics consulted by geneticists of the counseling unit and research and counseling department in 2006 and 2007 and 10 years later in 2016 and 2017. The total number of medical genetic cards processed during the 4 analyzed years was 14301 for all nosologies; the total number of cards of patients with DD or ID during the 4 years was 2321 cards. The total number of patients with DD or ID over the 4 analyzed years was 2350. Meanwhile the proportions of patients with DD or ID consulted in 2016-2017 increased significantly compared to the proportions of such patients consulted in 2006-2007. Results: During the research period (2006, 2007, 2016, and 2017) the structure of DD and ID remained almost unchanged for criteria such as gender and age. The proportions of patients with DD or ID caused by environmental factors and genetic causes also did not change. There was a significant increase in the number of patients with DD or ID in 2016 and 2017 with a diagnosis confirmed by biochemical, molecular genetic or cytogenetic methods. The number of nosological forms of PD and OA confirmed by molecular genetic or cytogenetic methods increased almost 5-fold over the ten-year period research. Conclusions: The significant increase in the number of patients with laboratory verified genetic forms of DD or ID in 2016 and 2017 is explained by significant advances in DNA diagnostics of syndromes manifesting in DD or ID, as well as the appearance of new research methods - chromosome microarray analysis and next-generation sequencing.

Objective: to study gene polymorphisms associated with the remodeling of the connective tissue of the eye as markers of preclinical diagnosis of primary open-angle glaucoma in patients with hereditary predisposition. Materials and methods: a total of 144 persons (56 men, 88 women), average age 59.3±6.2, were examined, not related, of Russian nationality. Group I consisted of 40 individuals suspected to affected by glaucoma, group II included 40 individuals with a diagnosis of I-II stage POAG in one or both eyes. Patients of both groups had a complicated family history of glaucoma. The control group consisted of 64 relatively healthy individuals. All patients underwent standard and special ophthalmological examination, as well as molecular genetic testing. Results: carriage of GT genotype and T allele of rs8136803 polymorphism (TIMP3), AG genotype and A allele of rs652438 polymorphism (MMP12), GA genotype and A allele of rs3825942 polymorphism (LOXL1) was associated with the development of POAG. The rs1048661 polymorphism of the LOXL1 gene cannot be considered as a marker of POAG development. Conclusion: the study indicates the need to develop a correct algorithm for diagnosing patients with POAG and suspected glaucoma with the inclusion of molecular genetic studies.

CBAVD syndrome (congenital bilateral aplasia of vas deferens) is a bilateral congenital aplasia of the VAS deferens, which is the main genetic cause of male infertility associated with obstructive azoospermia. CBAVD is heterogeneous in nature, in most cases, it is caused by pathogenic variants in the CFTR gene, mutations in other genes can be a rare cause. Although the phenotypic variability of congenital VAS deferens aplasia has been shown, including its morphological variants, the effect of the genotype on the state of the genitals and ejaculate parameters in patients with CBAVD syndrome has not been sufficiently studied. Aim: to evaluate the effect of the CFTR genotype on semen parameters in CBAVD syndrome patients. Materials and methods: a group of 74 unrelated Russian men of reproductive age with a diagnosis of CBAVD syndrome was examined. Molecular genetic analysis included the detection for 22 common pathogenic variants of the CFTR gene, and the IVS8-Tn polymorphic locus in intron 8. Semen analysis was performed in all patients. Results: Pathogenic variants of the CFTR gene were found in 51 of 148 (34,5%) alleles, IVS-T5 (5T) allele variant was revealed in 43 of 148 (29.1%) alleles. A comparative analysis of two groups of patients with pathogenic variants of the CFTR gene (group I) and without them (group II) was performed. Azoospermia was diagnosed in 62 of 74 (83.7%) patients, cryptozoospermia/severe oligozoospermia - in 12 (16.3%) patients. Oligospermia (ejaculate volume less than 1.5 ml) was found in groups I and II in 56 of 61 (91.8%) and 12 of 13 (92.3%) patients, respectively. Increased viscosity was observed in ejaculate samples in 4 (6.6%) patients of group I and 5 (38.5%) patients of group II. Leukospermia was found only in group II, in 3 (4.1%) patients. There were no statistically significant differences in semen parameters between the groups. Obtained data indicate that the CFTR genotype does not significantly affect semen parameters in CBAVD syndrome patients.

Krabbe’s disease (KD) is a rare inherited autosomal recessive lysosomal storage disease. KD is caused by mutations in the GALC gene leading to deficiency of galactosylceramidase. KD oссurs in 1 per 100 000 newborns, although some countries have a higher incidence rate. The exact KD incidence in Russia is unknown. A major mutation leading to the KD development is a large deletion affecting exons 11-17 of the GALC gene с.1161+6532_polyA+9kbdel (IVS10del30kb). This mutation occurs in 50% of KD cases in the European population. Patients from different regions were studied to analyze the mutation spectrum and the incidence in the Russian population. The incidence rate of the large deletion in our study equals 54%, that is comparable with European population. However, in the Chechen Republic this mutation is much more common than in other regions. 950 samples were studied, 7 heterozygous carriers of frequent mutation were identified. Thus, the estimated KD incidence rate is 1:51237 considering other mutations, and it is higher than that in the European population. Additional analysis of all detected GALC mutations revealed a genetic variant c.578T>C, p.Ile193Thr with allelic frequency measured up 8%. This substitution was described in our selection for the first time and presented only in Russian patients with late infantile form of the disease.

Insufficient accuracy of preoperative differential diagnostics by cytological examination of fine-needle aspiration biopsy material and low proportion of cases of malignant neoplasms described by molecular genetic markers with known diagnostic significance determine the relevance of the search for new molecular genetic markers with an assessment of their association with cancer risk and clinical and morphological characteristics. The aim of the work was to study the prevalence of an expanded spectrum of known and new putative driver and secondary mutations in benign and malignant thyroid neoplasms. Material: fresh frozen surgical material of malignant (64 samples) and benign (16 samples) thyroid neoplasms. Methods: search for point variants, short insertions/deletions, and copy number variations was performed via targeted high-throughput sequencing using AmpliSeq technology on the Illumina NextSeq platform. Fusions were by the presence of fused transcript by targeted high-throughput sequencing using AmpliSeq technology on the Illumina MiSeq platform. Results: mutations in genes BRAF, KRAS, NRAS, HRAS were detected in 62% of cancer cases. In 12% of cancers we detected rearrangements of CCDC6-RET (3 cases) and PAX8-PPARG (2 cases), TPM3-NTRK1, ETV6-NTRK3, STRN-ALK - one case each. In all cases, the identified rearrangements were mutually exclusive with other known driver mutations. In benign neoplasms, no rearrangements were found. Mutations in the TERT gene promoter have been identified in 10% of thyroid cancers and have been associated with known driver mutations. The well-known missense mutation EIF1AX was detected in one case of a benign neoplasm of the thyroid gland; in malignant neoplasms, no EIF1AX mutation were detected. Putative driver mutations in the PPM1D, PDGFRA, KDR oncogenes were detected in thyroid cancer samples and were not detected in benign thyroid neoplasms. Conclusions: the work characterize the prevalence of driver mutations with a known diagnostic significance and mutations in genes described in the literature without a known diagnostic significance in benign and malignant thyroid neoplasms.