In the last 10 years the biological three-dimensional model systems for long-term in vitro culture, similar in structure, performed functions and cellular composition with different organs - the organoids were developed. Currently, organoids represent a unique model for personalized treatment scheme selection, studying of fundamental processes and genetic, oncological and infectional diseases. Intestinal organoid cultures are utilized as a sensitive screening platform for estimation of CFTR channel functional properties, cystic fibrosis diagnostics and prescription of personalized treatment regimen for this disease.

Glycogen storage diseases (GSD) are a heterogeneous group of inherited defects of metabolism of glycogen. GSD du to phosphorylase kinase (PhK) deficiency named GSD IX is the most common of them. It belongs to liver GSDs and occurs in several subtypes that differ in mode of inheritance and tissue-specificity. PhK consists of several subunits coding by different genes. The genes PHKA2, PHKB and PHKG2 make the main contribution to GSD IX etiology. The aim of this study is analysis of genetic specify and genotype-phenotype correlations in patients with mutations in genes of PhK complex. 36 children with liver pathology from 30 unrelated families were studied. Using massively parallel sequencing technology 47 target genes with mutations resulted in liver pathology were analyzed in patients. In 28 patients 18 different hemizygous mutant alleles of PHKA2 were found. In 4 patients 5 homozygous or compound-heterozygous mutations of PHKG2 were detected. 14 PHKA2 variants and 3 PHKG2 variantss are novel. Heterozygous mutations of PHKB and PHKG2 were found in 3 and 1 pts respectively. Clinical significance of some variants in PHKA2, PHKB and PHKG2 is unclear. Most of detected mutations are missense-mutations. There are a few unclear cases with unreliable missense variants and variants in heterozygous state combined with ambiguous clinical features. The analysis of determined novel mutations and its possible effects on PhK complex shows that the finding of a rare variant is not ample for the diagnosis. Diagnosis confirmation must be based on complex study of all available data of frequencies, homology, gene structure and enzyme activity and combine analysis of genetic, clinical and laboratory features and signs.

Proteins of the ATP-binding cassette superfamily have important biological functions for active transmembrane transport of compounds, ion channels modulation in cells. Mutations in genes of this superfamily are responsible for the pool of hereditary diseases and cause the effect of multiple drug resistance response to chemotherapy as well. The frequency distribution of this functionally significant mutation in the multidrug resistance gene was analyzed in the present study. This is the first case of finding carriers of the ABCC11 gene 27-bp deletion in the ethnic groups of Russia. The revealed deletion allele frequency corresponds to 4.44% for the Aleuts and to 0.36% for the Kalmyks. The rest studied populations - Russians, Khants, Nivkhs, Mongols, Altaians were monomorphic for the absense of this (rs387906296) mutation. This study genotyping data were compared to the worldwide frequency distribution of the 27bp-deletion in the ABCC11 gene.

Nondystrophic myotonias are a group of muscle channelopathies. Mutations of CLCN1 and SCN4A genes cause the dysfunction of chloric and sodium ion channels. There are chloric channel myotonias (Thomsen’s and Becker’s types) and sodium channel myotonias (paramyotonia of Eulenburg, HyperkalemicPeriodic paralysis with myotonia, Potassium-aggravated myotonia, Myotonia fluctuans). Patients need in molecular-genetic testing for a right diagnose because some forms of nondystrophic myotonias are very similar. The aim of this work is to describe the spectrum of SCN4A mutations in Russian patients with sodium channel myotonias. The SCN4A mutations were revealed in 13 patients (54%). Five of these mutations were novel: c.205G>A (p.Gly69Arg), c.638G>A (p.Gly213Asp), c.2003T>C (p.Leu668Pro), c.2017C>G (p.Leu673Val), c.4137G>C (p.Gln1379His). All mutations were missense. Mutations in the exons 12, 13 и 22 of SCN4A gene account for 77% causes of sodium channel myotonias. The SCN4A mutations were found in patients with Thomsen’s myotonia (n = 4), paramyotonia of Eulenburg (n = 3), myotonia congenita (n = 2), Hyperkalemic Periodic paralysis (n = 2), Hypokalemic Periodic paralysis (n = 2). It is expediently to make molecular genetic analysis of SCN4A gene for patients with Thomsen’s myotonia and myotonia congenita.

The population frequency of alleles and genotypes CYP2C9*2 (rs12254292), *3 (rs9332108), *5 (rs1927465) и *6 (rs12254292); CYP2C19 (rs11187240); VKORC1 (rs9923231), (rs9934438); CYP4F2 (rs2108622); EPHX1 (rs7542242); GGCX (rs12616455); PROC (rs11887389), associated with the effectiveness of anticoagulant therapy with vitamin K antagonists in the Kazakh population was studied. Population sample was 2230 conditionally healthy Kazakhs. In the Kazakh population, the distribution of genotypes of 11 SNPs is in accordance with the Hardy-Weinberg equilibrium (p>0.05), with the exception of CYP2C9*3 (р<0.05). A comparative analysis showed that the CYP2C9*3, CYP2C9*5, CYP2C9*6, adverse alleles of the gene VKORC1 (rs9923231; rs9934438) and GGCX (rs11676382) alleles frequencies occupy an intermediate position between the previously described populations of Europe and Asia. The frequency of the minor alleles CYP2C9*2, CYP2C19, PROC (rs2069910) in the Kazakh population did not differ from the European populations, but significantly differs from the population of South Asia.

Sporadic angiomyolipoma of the kidney is the most common type of renal benign tumors with an estimated frequency of 1 case per 250 people. Despite the asymptomatic course, with the increase of the tumor size, the risk of rupture of micro- and macroaneurysms also increases, which threatens the patient’s life. The use of mTOR protein kinase inhibitors leads to tumor reduction. However, such drugs are prescribed only if the patient has a somatic or germline mutation in the TSC1 or TSC2 genes the products of which are endogenous mTOR inhibitors in the reaction cascade of the PI3K/Akt/mTOR pathway. According to the COSMIC database, driver mutations in the TSC1 and TSC2 genes were identified only in 57% of angiomyolipoma cases, whereas the causes of the remaining cases are still not clear. We have conducted a loss of heterozygosity (LOH) screening in 20 sporadic kidney AML samples by use of the NGS. In seven of the twenty samples, LOH was found in different chromosome regions. In five samples, LOH encompasses the 16p13.3 region, where the TSC2 gene is located. In two samples with the normal allelic state of the 16p13.3 region, we have detected alternative LOH events encompassing 15q14q15.1 in one case, and multiple chromosomal regions in another (high chromosomal instability).