Background: Despite the high progress that has been made in the field of cardiology, the left ventricular assist device (LVAD) can still cause complications (thrombosis/bleeding) in heart failure (HF) patients after implantation. Complications develop due to the incorrect dose of antithrombotic therapy, due to the influence of the non-physiological shear stress of the device, and also due to inherited genetic polymorphisms. Therefore, the aim of our study is to identify the influence of the genetic polymorphisms on complication development in HF patients with implanted LVADs with prescribed antiplatelet therapy. Methods: Our study investigated 98 HF patients with/without complications who were genotyped for 21 single-nucleotide polymorphisms (SNPs) associated with cardiovascular events, the coagulation system, and the metabolism of warfarin and aspirin drugs. This study performed a more detailed analysis on genetic polymorphism in the UGT1A6 gene and its influence on aspirin dose. Results: SNP rs2070959 in the UGT1A6 gene showed a significant association with the group of HF patients with complications [(OR (95% CI): 4.40 (1.06-18.20), p = 0.044]. The genetic polymorphism of rs2070959 in the UGT1A6 gene showed a significant association in HF patients who received aspirin treatment on the 12th month after LVAD implantation [OR (95% CI): 5.10 (1.31-19.87), p = 0.018]. Moreover, our genotype distribution analysis showed that the GG genotype of rs2070959 in the UGT1A6 gene was significantly higher in the group with aspirin treatment than without treatment after the 12th month of treatment (50.0% vs. 0%, p = 0.008), especially in the group of patients with complications. A higher frequency of the GG genotype with long-lasting aspirin therapy up to the 12th month showed that 100 mg of aspirin was not an effective dose in the group of patients with complications. Conclusions: Our study identified that genotyping for genetic polymorphism rs2070959 in the UGT1A6 gene could predict the recommended dose of aspirin in HF patients, which could help to prevent and predict complication development after LVAD implantation.

Low vitamin D status is linked to disturbance in cognitive performance. This study explored possible ways how composition and functional capacity of the gut microbiome affects vitamin D metabolism, directing serum vitamin D (VitD) levels and memory impairmets. It was found that gut microbiome composition, characterized by an increase in the relative abundance of Enterococcus and correlated with vitamin D deficiency and, as consequence, with memory impairments. A key mechanism identified in the study was the differential utilization of short-chain fatty acids (SCFAs) produced by gut bacteria as substrates for synthesizing vitamin D3 precursor in the skin. This finding confirms a complex interplay between the gut microbiome, host metabolism, and cognitive health, highlighting the potential significance of targeting Enterococcus dysbiosis in future preventive and therapeutic strategies to address VitD deficiency-related memory impairments. These results underscore the importance of understanding and modulating gut microbiome composition to optimize VitD status and cognitive function.

OBJECTIVE:Tuberculosis is a major health problem in many countries, including Kazakhstan. Host genetics can affect TB risk, and epidemiological and social factors may contribute to disease progression. Due to the high incidence of pulmonary tuberculosis in the country, our research aimed to study the epidemiological and genetic aspects of pulmonary tuberculosis in Kazakhstan. MATERIAL AND METHODS:1026 participants of Central Asian origin were recruited in the study: 342 individuals diagnosed with active PTB, 342 household contacts, and 342 controls without a family history of TB. Genetic polymorphisms of selected genes were determined by real-time polymerase chain reaction. The association between the risk of pulmonary TB and polymorphisms was evaluated using logistic regression and assessed with the ORs and their corresponding 95 % CIs, and the significance level was determined as p < 0.05. RESULTS:Epidemiological data revealed that underweight BMI (χ² = 89.97, p < 0.001), employment (χ² = 39.28, p < 0.001), and diabetes (χ² = 12.38, p < 0.001) showed a significant association with PTB. A/T polymorphism of the IFG gene showed a lower risk, and A/A polymorphism showed an increased risk of susceptibility to TB. A/A polymorphism of the IFG gene was associated with an almost 3-fold increased risk of PTB, and A/T polymorphism of the IFG gene was associated with a decreased risk of PTB (OR = 0.67, 95 % CI = 0.49-0.92, p = 0.01). The analysis revealed a decreased risk of PTB for A/A polymorphism of the VDR ApaI (OR = 0.67, 95 % CI = 0.46-0.97, p < 0.05). A/A polymorphism of the TLR8 gene was associated with a 1.5-fold increased risk of PTB (OR = 1.53, 95 % CI = 1.00-2.33, p < 0.05). CONCLUSION:Results showed that gender, employment, underweight BMI and diabetes are associated with PTB incidence in our study cohort. The A/A genotype of the IFG (rs2430561) and an A/A genotype of the TLR8 (rs3764880) genes were associated with an increased risk of PTB. A/T polymorphism of the IFG (rs2430561) and A/A polymorphism of the VDR ApaI were associated with a decreased risk of PTB.

In Kazakhstan, there is insufficient data on genetic epilepsy, which has its own clinical and management implications. Thus, this study aimed to use whole genome sequencing to identify and evaluate genetic variants and genetic structure of early onset epilepsy in the Kazakhstani pediatric population. In this study, for the first time in Kazakhstan, whole genome sequencing was carried out among epilepsy diagnosed children. The study involved 20 pediatric patients with early onset epilepsy and no established cause of the disease during the July–December, 2021. The average age at enrolment was 34.5 months, with a mean age at seizure onset of 6 months. Six patients (30%) were male, and 7 were familial cases. We identified pathogenic and likely pathogenic variants in 14 (70%) cases, among them, 6 novel disease gene variants ( KCNQ2 , CASK , WWOX , MT-CO3 , GRIN2D , and SLC12A5 ). Other genes associated with the disease were SCN1A (x2), SLC2A1 , ARX , CACNA1B , PCDH19 , KCNT1 , and CHRNA2 . Identification of the genetic causes in 70% of cases confirms the general structure of the etiology of early onset epilepsy and the necessity of using NGS in diagnostics. Moreover, the study describes new genotype-phenotypic correlations in genetic epilepsy. Despite certain limitations of the study, it can be concluded that the genetic etiology of pediatric epilepsy in Kazakhstan is very broad and requires further research.

Purpose: Congestive heart failure (HF) is a heterogeneous life-threatening syndrome. Heart transplantation (HT) is one of the gold standard treatment at the end-stage of HF. On the other hand, implantation of the mechanical circulatory support (MCS) device is an alternative treatment which improves patient's quality of life. However, HF patients have development of the thrombosis and bleeding complications due to the non-physiologic shear-stress and incorrect dosage of antiplatelet drugs. The aim of our research was to identify influence of UGT1A6 gene polymorphism and its impact on the development of the complications in HF patients after MCS implantation.

Background: Tuberculosis (TB) and vitamin D deficiency remain major public health problems in Kazakhstan. Due to the high incidence of pulmonary tuberculosis in the country and based on the importance of vitamin D in the modulation of the immune response and the association of its deficiency with many health conditions, the aim of our research was to study the vitamin D status, VDR and TLR gene polymorphisms, and pulmonary tuberculosis epidemiology in Kazakhstan. Methods: A case-control study included 411 individuals diagnosed with pulmonary TB and 686 controls with no family history of pulmonary tuberculosis. Concentrations of serum vitamin D (25-(OH)D) levels were measured by electrochemiluminescence immunoassay. The gene polymorphisms were determined by real-time polymerase chain reaction (PCR) allelic discrimination assay using TaqMan probes. The association between the risk of pulmonary TB and polymorphisms was evaluated using multimodal logistic regression and assessed with the ORs, corresponding to 95% Cis, and the significance level was determined as p < 0.05. Results: 1097 individuals were recruited from 3 different regions of Kazakhstan. Biochemical data showed vitamin D deficiency (25-(OH)D < 20 ng/mL) was present in both groups, with the case group accounting for almost 95% and 43.7% in controls. Epidemiological data revealed that socioeconomic factors such as BMI < 25 kg/m2 (p < 0.001), employment (p < 0.001), diabetes (p < 0.001), and vitamin D deficiency (p < 0.001) were statistically different between case and control groups. Logistic regression analysis, adjusted by sex, age, BMI, residence, employment, smoking, alcohol consumption, and diabetes, showed that T/T polymorphism of the VDR gene (rs1544410, OR = 1.97, 95% CI: 1.04–3.72, p = 0.03) and A/A polymorphism of the TLR8 gene (rs3764880, OR = 2.44, 95% CI: 1.20–4.98, p = 0.01) were associated with a high risk of developing pulmonary tuberculosis. Conclusions: Vitamin D deficiency remains prevalent in our study cohort and is associated with TB progression. Socioeconomic determinants such as unemployment, BMI under 25 kg/m2, and diabetes are the main risk factors for the development of pulmonary TB in our study. A/A polymorphism of TLR8 (rs3764880) and T/T polymorphism (BsmI, rs1544410) of VDR genes may act as biomarkers for pulmonary tuberculosis in the Kazakh population.

Introduction. Sitosterolemia is a rare genetic disorder directly associated with dysfunction of ABCG5 and G8 genes. The data obtained was used to analyze the cellular mechanisms and the role of transporters in absorption and excretion of serum sterols. Thus, to understand the influence of mutations on the development of cardiovascular disease. Aim. To investigate the clinical manifestation between sitosterolemia and familial hypercholesterolemia (FH), focusing on how dysfunctions of transporters lead to the misdiagnosis of sitosterolemia as FH. Research Strategy.The data collection was conducted by searching research papers in English based on lipidology. The search strategy identified 118 papers, of which 42 were selected that meet established inclusion criteria: full-text publications in English, meta-analyses, cohort studies, experiments on mice, whereas established exclusion criteria: research papers in other languages, promotional articles, conferences, short reports. The research papers reviewed the span from 1970 to 2022. Results. Inactivation of genes causes the dysregulation of sterols. FH is characterized by elevated low-density lipoprotein cholesterol (LDL-C), whereas sitosterolemia presents with moderate elevation in LDL-C but dramatic increase in phytosterols. The phenotypic overlap between sitosterolemia and FH complicates detection. Both disorders manifest cardiovascular complications with elevated total cholesterol (TC) levels. The lipid profile distinguishes these conditions, necessitating HPLC, GC-MS tools. Genetic testing for mutations is essential for confirmation. The findings suggest that sitosterolemia mimics the FH state. FH is managed primarily with statins, while sitosterolemia requires ezetimibe. In addition, dietary modifications that reduce the intake of plant sterols are recommended. Conclusion. This review highlights ABCG5 and ABCG8 mutations that impair sterol transport, causing plant sterol accumulation. The condition often leads to xanthomas and early coronary artery disease. A major diagnostic challenge is the overlap with FH, as similar lipid abnormalities can obscure proper diagnosis. Введение. Ситостеролемия - это редкое генетическое заболевание, непосредственно связанное с дисфункцией генов ABCG5 и ABCG8. Полученные данные использовались для анализа клеточных механизмов и роли транспортёров в абсорбции и выведении стеролов из организма. Таким образом, целью исследования является понимание влияния мутаций на развитие сердечно-сосудистых заболеваний. Цель. Изучить клинические проявления ситостеролемии и семейной гиперхолестеринемии (СГ), с акцентом на то, как дисфункции транспортёров приводят к ошибочной диагнозу ситостеролемии как СГ. Стратегия поиска. Сбор данных осуществлялся путём поиска научных статей на английском языке, посвящённых липидологии. В ходе поиска было выявлено 118 публикаций, из которых 42 статьи соответствовали установленным критериям включения: полнотекстовые публикации на английском языке, метаанализы, исследования пациентов, эксперименты на мышах. Исключались статьи на других языках, рекламные материалы, материалы конференций и краткие отчёты. Обзор охватывал исследования, опубликованные в период с 1970 по 2022 годы. Результаты. Инактивация генов приводит к дисрегуляции транспорта стеролов. Для СГ характерно повышение уровня липопротеинов низкой плотности (ЛПНП), в то время как ситостеролемия сопровождается умеренным увеличением ЛПНП, но значительным повышением уровня фитостеролов. Фенотипическое сходство между ситостеролемией и СГ затрудняет их диагностику. Оба заболевания сопровождаются сердечно-сосудистыми осложнениями и повышением общего холестерина (ОХ). Липидный профиль позволяет различать эти состояния, для чего требуются такие методы, как ВЭЖХ и ГХ-МС. Генетическое тестирование на наличие мутаций является необходимым для подтверждения диагноза. Полученные данные показывают, что ситостеролемия имитирует состояние, схожее с СГ. Основной метод лечения СГ — использование статинов, тогда как для ситостеролемии требуется назначение эзетимиба. Кроме того, рекомендуется изменение рациона с ограничением потребления растительных стеролов. Вывод. Обзор подчеркивает, что мутации в генах ABCG5 и ABCG8, нарушающие транспорт стеролов, вызывают накопление растительных стеролов. Заболевание часто приводит к развитию ксантом и раннему поражению коронарных артерий. Основной диагностической проблемой является сходство с СГ, так как схожие липидные нарушения затрудняют постановку правильного диагноза. Кіріспе. Ситостеролемия – ABCG5 және ABCG8 гендерінің дисфункциясымен тікелей байланысты сирек кездесетін генетикалық ауру. Алынған деректер жасушалық механизмдер мен стеролдардың сіңуі мен шығарылуындағы тасымалдаушылардың рөлін талдауға пайдаланылды. Осылайша, мутациялардың жүрек-қан тамырлары ауруларының дамуына әсерін түсінуге болады. Мақсат. Ситостеролемия мен отбасылық гиперхолестеринемияның клиникалық көріністерін зерттеу, соның ішінде тасымалдаушылардың дисфункциялары ситостеролемияны отбасылықгиперхолестеринемия ретінде қате диагностикаға қалай әкелетінін талдау. Іздеу стратегиясы. Мәліметтер жинау липидология саласындағы ағылшын тіліндегі ғылыми мақалаларды іздеу арқылы жүзеге асырылды. Іздеу нәтижесінде 118 жарияланым анықталып, олардың 42-сі іріктеу критерийлеріне сәйкес келді: толық мәтінді ағылшын тіліндегі мақалалар, метаанализдер, когорттық зерттеулер, тышқандармен эксперименттер. Іріктеу критерийлеріне сәйкес келмегендер: басқа тілдердегі зерттеулер, жарнамалық материалдар, конференция материалдары және қысқаша есептер. Зерттеулер 1970-2022 жылдар аралығын қамтыды. Нәтижелер. Гендердің инактивациясы стеролдардың реттелуін бұзады. Отбасылық гиперхолестеринемия кезінде төмен тығыздықтағы липопротеидтердің (ТТЛП) деңгейі жоғарылайды, ал ситостеролемия кезінде ТТЛП деңгейі орташа деңгейде болса да, фитостеролдардың күрт өсуі байқалады. Ситостеролемия мен отбасылық гиперхолестеринемия арасындағы фенотиптік ұқсастық олардың диагностикасын қиындатады. Екі ауру да жалпы холестериннің (ЖХ) жоғарылауымен және жүрек-қан тамырлары асқынуларымен сипатталады. Бұл жағдайларды ажырату үшін липидті профиль қажет, ол үшін HPLC және GC-MS әдістері қолданылады. Диагнозды растау үшін мутацияларға генетикалық тестілеу жүргізу өте маңызды. Алынған деректерге сүйенсек, ситостеролемия отбасылық гиперхолестеринемияға ұқсас жағдайды имитациялайды. Отбасылық гиперхолестеринемияны емдеуде статиндер негізгі құрал болып табылады, ал ситостеролемия жағдайында эзетимиб тағайындалады. Сонымен қатар, өсімдік стеролдарын тұтынуды шектеуге бағытталған диета ұсынылады. Қорытынды. Бұл шолу стеролдардың тасымалдануын бұзатын ABCG5 және ABCG8 гендеріндегі мутациялар өсімдік стеролдарының жиналуына әкелетінін атап көрсетеді. Ауру ксантоманың пайда болуына және жүрек артерияларының ерте зақымдануына жиі себеп болады. Негізгі диагностикалық қиындық – бұл отбасылық гиперхолестеринемиямен ұқсастығы, өйткені ұқсас липидті өзгерістер дұрыс диагноз қоюды қиындатады.

Clonal hematopoiesis (CH) is the increase in somatic clones carrying mutations in hematopoietic stem cells. This biological condition can lead to cancer and is implicated in the development of atherosclerosis and cardiovascular diseases. CH of indeterminate potential (CHIP) refers to somatic mutations in genes that are associated with the development of Coronary heart disease (CHD) and leukemia. Now, with next-generation sequencing, we can detect mutations even if they are present in only a small number of cells in the tissue sample being studied. Consequently, numerous studies have shown that mutations in the DNMT3A, TET2, ASXL1, and JAK2 genes found in the blood are associated with coronary heart disease. The purpose of our study is to detect a genetic variant of genes in Kazakh patients with atherosclerosis, which will further allow us to study the role of CHIP in increasing the risk of developing coronary microvascular dysfunction and CHD. We perform high-throughput whole-exome sequencing in patients with atherosclerosis. The object of the study is samples delivered from the clinic “National Scientific Cardiac Surgery Center” in Astana. The study is carried out in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Genomic DNA extraction was performed on 245 samples using the Illustra Blood Kit (Cytiva, USA). Qualitative and quantitative assessment of the extracted genomic DNA was conducted using the NanoDrop 2000 (Thermo Scientific) and Qubit 2.0 (Thermo Fisher Scientific). Subsequently, DNA library preparation was carried out using the Illumina DNA Prep with Exome 2.5 Enrichment kit. Quality control of the resulting DNA libraries was conducted on a 2100 Bioanalyzer system using the Agilent DNA 1000 Kit and High Sensitivity DNA kit (Agilent Technologies). Following assessment of the DNA library concentration on Qubit 2.0, they were loaded onto the high-performance sequencer NovaSeq 6000 (Illumina, USA) following the manufacturer’s protocol. We conducted human whole-exome sequencing on 245 samples to identify somatic clones in the peripheral blood of patients with atherosclerosis. Patients were divided into three groups – low risk, middle, and high risk of atherosclerotic complications. Bioinformatic analysis of sequence data were performed. We created list of genes associated with CH to deep analysis and to interpreter the data in patient groups. Subsequently, DNA extraction from the remaining samples is performed, followed by sequencing on the NovaSeq 6000 platform. Analysis of the resulting sequenced data is currently underway. Further research and monitoring of CHIP will enable us to understand the mechanisms underlying the development of cardiovascular diseases and to devise a comprehensive management plan for patients with this pathology. Supported by Committee of Science of the Ministry of Science and Higher Education of Republic of Kazakhstan (AP14869903), (BR21881970) and Nazarbayev University CRP (211123CRP1608).

Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer in Central Asia, often diagnosed at advanced stages. Understanding population-specific patterns of ESCC is crucial for tailored treatments. This study aimed to unravel ESCC’s genetic basis in Kazakhstani patients and identify potential biomarkers for early diagnosis and targeted therapies. ESCC patients from Kazakhstan were studied. We analyzed histological subtypes and conducted in-depth transcriptome sequencing. Differential gene expression analysis was performed, and significantly dysregulated pathways were identified using KEGG pathway analysis (p-value < 0.05). Protein-protein interaction networks were constructed to elucidate key modules and their functions. Among Kazakhstani patients, ESCC with moderate dysplasia was the most prevalent subtype. We identified 42 significantly upregulated and two significantly downregulated KEGG pathways, highlighting molecular mechanisms driving ESCC pathogenesis. Immune-related pathways, such as viral protein interaction with cytokines, rheumatoid arthritis, and oxidative phosphorylation, were elevated, suggesting immune system involvement. Conversely, downregulated pathways were associated with extracellular matrix degradation, crucial in cancer invasion and metastasis. Protein-protein interaction network analysis revealed four distinct modules with specific functions, implicating pathways in esophageal cancer development. High-throughput transcriptome sequencing elucidated critical molecular pathways underlying esophageal carcinogenesis in Kazakhstani patients. Insights into dysregulated pathways offer potential for early diagnosis and precision treatment strategies for ESCC. Understanding population-specific patterns is essential for personalized approaches to ESCC management.

Familial hypercholesterolemia (FH) is a serious inherited disorder that can lead to early development of cardiovascular disease (CVD) due to the high blood cholesterol levels. In our study, we identified in FH patient likely pathogenic variant of LDLR and APOE genes. Interest in the homozygous state of FH is understandable given its rarity and severe health consequences. The homozygous state, when both LDL receptor alleles mutated, demonstrates even higher cholesterol levels and an earlier and more severe clinical course compared with the heterozygous state. In our study, we report an interesting case of homozygous FH due to its rare prevalence. Patient U., 16 years old, woman, admitted to the National Research Cardiac Surgery Center (NRCC), was diagnosed with FH, congenital heart disease (CHD), bicuspidal aortic valve (AV) type 1. Both parents (mother and father) were included for reliable analysis. DNA was isolated from the venous blood sample by using the column method of QIAamp DNA Mini Kit. Targeted NGS using TruSight Cardio panel for 174 genes was performed on MiSeq, Illumina. Identified genetic variants were classified according to the ACMG guidelines. Pathogenic variants were validated by Sanger sequencing. Additionally, databases of the VarSome and ClinVar were used for analysis. Sequencing of 96 genes and bioinformatics analysis identified 2 likely pathogenic variants - C526T:p.R176C in APOE and G295A:p.E99K in LDLR gene, 4 uncertain significance variants in APOB, TTN, COL3A1, NOTCH1 and 90 benign variants in APOB, TTN, LAMA4, MYPN, DMD. LDLR (G295A:p.E99K) and APOE (C526T:p.R176C) were validated and confirmed by Sanger sequencing in patients and her father and mother. The main function of the APOE gene is to make the protein apolipoprotein E, which is involved in fat metabolism. In our study, the patient had a heterozygous variant of СT polymorphism rs7412 in the APOE gene, which indicates the presence of a possible disorder of fat metabolism. LDLR gene encodes a protein called low-density lipoprotein receptor, which is responsible for the uptake of cholesterol-carrying lipoprotein particles in cells. In our study, a patient with a homozygous AA variant of the LDLR gene was found to be pathogenic. Disruption of the uptake of cholesterol-carrying lipoprotein particles in cells can have serious consequences for the body. This can lead to cholesterol accumulation in the blood and tissues, which in turn can contribute to the development of atherosclerosis and other CVD. We found that both parents had a heterozygous genotype of G295A:p.E99K in LDLR gene; and mother had a heterozygous genotype and father had a homozygous genotype of C526T:p.R176C in APOE gene. In our study, we found the genetic mutations - two likely pathogenic genetic variants LDLR (G295A:p.E99K) and APOE (C526T:p.R176C) associated with FH in patient with clinical phenotype of FH using TruSight Cardio targeted panel of 96 genes. Genetic testing using targeted NGS or whole exome sequencing would be useful for right diagnosis and might improve personalize treatment for these patients. To identify other genes associated with FH whole exome sequencing can be recommend. Supported by Committee of Science of the Ministry of Science and Higher Education of Republic of Kazakhstan (AP14869903), (BR21881970) and Nazarbayev University CRP (211123CRP1608).

Introduction. Cardiac arrhythmias are the most common among the group of cardiovascular diseases (CVD), and have a risk of sudden cardiac death (SCD). Long QT syndrome (LQTS) is a heritable disease characterized by prolongation of the QT interval on an electrocardiogram (ECG), which often leads to syncope and SCD. Currently, identification of mutations in cardiac ion channel genes in patients with LQTS and recognition of genetic causes of the syndrome are actual in cardiology. Aim. To identify cardiac ion channel mutations in genes associated with long QT syndrome in Kazakhstani patients. Materials and methods.This study was designed as a cohort study. At present, our study has identified three patients with LQTS. Nevertheless, the recruitment of additional patients with LQTS for the study is ongoing. Illumina TruSight Cardio panel was used for genetic screening. The cardiopanel consists of 174 genes associated with cardiac disorders including LQTS. After a targeted sequencing, data analysis was carried out using the programs SureCall version 2.0.7.0 (Agilent Technologies, Santa Clara, California, USA), ANNOVAR, GTK, bwa, bowtie, bow tie 2, VarScan, etc. Results. Clinically significant variants were found in patients with LQTS. Namely, in genes SCN5A (c.G5296A:p.E1766K) and KCNH2 (c.C662T:p.A221V). Both variants are pathogenic and cause CVDs, specifically LQTS. In addition, c.G3785A mutation (p.R1262Q), a variant of uncertain significance in SCN5A gene was detected in one patient. Although there is insufficient data to determine the role of the variant in development of the disease. Conclusions. Screening for mutations in cardiac ion channel genes in patients with LQTS revealed clinically significant mutations. This research will be useful for Kazakhstani patients with LQTS in evaluation of required genetic testing and reliable genetic guidance to prevent SCD and distinguish between various arrhythmias. Введение. Сердечные аритмии являются наиболее распространенным заболеванием в группе сердечно-сосудистых заболеваний (ССЗ) и имеют риск внезапной сердечной смерти (ВСС). Синдром удлиненного интервала QT (СУИQT) является наследственным заболеванием, характеризующимся удлинением интервала QT на электрокардиограмме (ЭКГ), что часто приводит к обмороку и ВСС. В настоящее время идентификация мутаций в генах сердечных ионных каналов у пациентов с СУИQT и определение генетических причин синдрома актуальны в кардиологии. Цель. Определить мутации сердечных ионных каналов в генах, связанных с СУИQT у пациентов из Казахстана. Материалы и методы. Это исследование разработано в форме когортного исследования. На данный момент наше исследование выявило трех пациентов с СУИQT. Тем не менее, дальнейший набор пациентов для исследования продолжается. Для генетического скрининга использовалась панель – Illumina TruSight Cardio panel. Кардиопанель состоит из 174 генов, связанных с сердечно-сосудистыми нарушениями, включая СУИQT. После таргетного секвенирования был проведен анализ данных с использованием ряда программ SureCall версии 2.0.7.0 (Agilent Technologies, Санта-Клара, Калифорния, США), ANNOVAR, GTK, bwa, bowtie, bow tie 2, VarScan и т.д. Результаты. Клинически значимые варианты были обнаружены у пациентов с СУИQT. А именно, в генах SCN5A (c.G5296A:p.E1766K) и KCNH2 (c.C662T:p.A221V). Оба варианта являются патогенными и вызывают ССЗ, в частности, СУИQT. Кроме того, у одного пациента была обнаружена мутация c.G3785A (p.R1262Q), вариант неопределенной значимости в гене SCN5A. Однако, на сегодняшний день недостаточно данных для определения роли варианта в развитии заболевания. Выводы. Скрининг мутаций в генах сердечных ионных каналов у пациентов с СУИQT выявил клинически значимые мутации. Это исследование будет полезным для казахстанских пациентов с СУИQT для оценки необходимого генетического тестирования и надежного генетического консультирования для предотвращения ВСС и идентификации определенной аритмий. Кіріспе. Жүрек аритмиясы жүрек-қан тамырлары аурулары (ЖҚА) тобында ең көп таралған ауру болып табылады және кенеттен жүрек өлімі (КЖӨ) қаупін тудырады. Ұзартылған QT синдромы (LQTS) - электрокардиограммадағы (ЭКГ) QT аралығының ұзаруымен сипатталатын тұқым қуалайтын ауру, бұл жиі естен тануға және КЖӨ -не әкеледі. Қазіргі уақытта LQTS пациенттеріндегі жүректегі иондық канал гендеріндегі мутацияларды анықтау және синдромның генетикалық себептерін анықтау кардиологияда өзекті мәселе болып табылады. Мақсаты. Қазақстандық пациенттерде LQTS-мен байланысты жүректің иондық канал гендердегі мутацияларын анықтау. Материалдар мен әдістер. Бұл зерттеу когортты зерттеу түрінде жасалған. Осы уақытқа дейін біздің зерттеуіміз LQTS бар үш науқасты анықтады. Дегенмен, пациенттерді зерттеуге одан әрі іліктеу жалғасуда. Генетикалық скрининг жасау мақсатында Illumina TruSight Cardio панелі қолданылды. Кардиопанель жүрек-қан тамырлары ауытқуларымен байланысты 174 геннен тұрады, соның ішіне LQTS те кіреді. Таргетті секвенирлеуден кейін бірқатар бағдарламалар SureCall 2.0.7.0 (Agilent Technologies, Санта-Клара, Калифорния, АҚШ), ANNOVAR, GTK, bwa, bowtie, bow tie 2, VarScan және т. б. қолдана отырып, деректерді талдау жүргізілді. Нәтижелері. LQTS бар науқастарда клиникалық маңызды генетикалық варианттар табылды. Атап айтқанда, SCN5A (с.G5296A:р.E1766K) және KCNH2 (c.C662T:р.A221V) гендерінде. Жоғарыда аталған екі генетикалық вариант патогенді болып келеді, және де ЖҚА ішінде LQTS тудырады. Сонымен қатар, бір пациентте c.G3785A (p.R1262Q) мутациясы анықталды, бұл SCN5A геніндегі белгісіз маңыздылық вариантына жатады. Алайда, бүгінгі күнге дейін варианттың ауру дамуындағы рөлін анықтау үшін деректер жеткіліксіз болып келеді. Қорытынды. LQTS пациенттеріндегі жүректегі иондық канал гендеріндегі скрининг клиникалық маңызды мутацияларды анықтады. Бұл зерттеу қазақстандық LQTS пациенттері үшін қажетті генетикалық тестілеуді бағалаумен қатар, КЖӨ-ін алдын алу және белгілі аритмияны анықтау шаралары үшін пайдалы болып табылады.

Purpose: Sudden cardiac death (SCD) is an important cause of mortality worldwide. While coronary artery disease accounts for the majority of SCD in the elderly population, inherited cardiac diseases (inherited CDs) comprise a substantial proportion of younger SCD victims with a significant genetic component. In many cases, autopsy reveals unspecific and inconclusive results, like idiopathic left ventricular hypertrophy, nonsignificant coronary atherosclerosis, and primary myocardial fibrosis. Their pathogenicity and their relation to SCD cause is unknown.

Epilepsy is one of the most common neurological disorders affecting approximately 50 million people worldwide. It impacts people of all genders and ages, but evidence suggests a higher incidence rate in children and the elderly. Given that childhood epilepsy has the risk of causing developmental epileptic encephalopathy, which is associated with intellectual, behavioral, and/or motor disabilities, proper assessment of children with new-onset epilepsy at an early stage is essential to prevent threats affecting neurodevelopmental processes. The aim of this study was to investigate whole genome sequencing data of children diagnosed with epilepsy. Our results revealed an identification of a novel mutation in a 2-year-old male patient who suffered from recurrent epileptic seizures of unknown etiology. The detected variant is heterozygous and located in gene CHRNA2 (chr8:27321348, NM_000742, c.612G > A, p.Trp204∗) in exon 6. The databases such as Varsome, GeneCards, and NCBI did not reveal any matches with previously identified variants, implying the novelty of the finding. Moreover, according to various prediction tools (MutationTaster, SIFT, CADD, FATHMM-MKL, LRT, DANN, Eigen, and BayesDel), the mutation is characterized as pathogenic, which corresponds to the American College of Medical Genetics and Genomics (ACMG) classification. According to the findings, mutation of the CHRNA2 gene is closely associated with two disorders known as autosomal dominant nocturnal frontal epilepsy (ADNFLE), and benign familial infantile epilepsy (BFIS). Comparison of proband's clinical manifestations showed that it is difficult to attribute precisely the patient's symptoms to either of the conditions, however the evidence suggests that the patient's symptoms are more consistent with those of ADNFLE. In this report, we expanded the spectrum of existing variations in the CHRNA2 gene contributing and associated with the development of epilepsy with the important and novel causative genetic variant.

Mutations in genes encoding cardiac ion channels can cause dangerous cardiac conditions. Channelopathies are disorders that occurs due to dysfunction of ion channels. Cardiac channelopathies affect at least 1:1000 people, clinically appearing in various cardiac arrhythmias, seizures, syncope, sudden cardiac death (SCD), etc. The purpose of our study is to compare ion channel genes mutations found in SCD victims and cardiac patients by using targeted Next-generation sequencing (NGS). Thirty-six individuals who died from SCD and 9 patients with cardiac disorders: primary electrical diseases (PED) and cardiomyopathies (CMP) were included in our study. We sequenced all coding regions of 174 cardiac risk genes by targeted NGS on Illumina MiSeq platform. Illumina TruSight Cardio panel was used for genetic screening. The clinical significance of variants classified by ACMG/AMP guidelines. In addition, InterVar and ClinVar databases were applied for variant interpretation. A total of 43 variants associated with ion flux were identified in our study group. Annotated data demonstrated 2.3% and 4.6% likely pathogenic, 32.5% and 16.3% variants of uncertain significance (VUS), 13.9% and 2.3% likely benign, also 30.2% benign variants according to ACMG classification for SCD cases verse cardiac patients, respectively. Mostly ion channel mutations detected in genes SCN5A, RYR2, CACNA1C, SCN1B, KCNH2, KCND3, KCNE1, KCNA5 and KCNJ2. Notably, KCND3 (p.D150H) variant is likely pathogenic, identified in SCD victim who was diagnosed with secondary cardiomyopathy postmortem. Another missense-mutation SCN5A (p.E1596K) belongs to likely pathogenic variant, detected in cardiac patients’ group. Likely pathogenic variant KCNH2 (p.A221V) identified in patients with cardiac disorders. In our research we found out clinically significant variants within 174 cardiac genes associated with cardiac disorders. Genetic screening revealed a high rate of variants of uncertain significance in ion flux, underscoring the need for further clinical and functional studies. Nevertheless, targeted NGS screening in ion channel genes contribute further evaluation of forensic investigation. Study was supported by Committee of Science of the Ministry of Science and Higher Education of the Republic of Kazakhstan (AP14869903) and Nazarbayev University, CRP (211123CRP1608).