In order to improve the diagnosis of arrhythmogenic cardiomyopathy (ACM) in 2023, leading European experts validated new recommendations and a consensus report with augmented criteria for diagnosis of ACM (based on modified ITF criteria 2010 and Padua criteria 2020). The article highlights the crucial aspects of diagnosis and practical experience of novel criteria for the recognition of various phenotypes of ACM.

Введение. Синдром Марфана (СМ) – одно из часто встречающихся заболеваний группы наследственных нарушений (дисплазий) соединительной ткани с распространенностью в популяции 2-3 случая на 10000 человек. Продолжительность жизни пациентов ограничивается поражениями сердечно-сосудистой системы – развитием острого расслоения грудной аорты. Диагноз устанавливается на основании Гентских критериев (2010), в которых основополагающим является обнаружение патогенной мутации в гене FBN1. В гене, расположенном на 15-й хромосоме и содержащем 66 экзонов (из них 65 кодирующих), на данный момент насчитывается более 3000 нуклеотидных вариантов. Базы данных патогенных мутаций постоянно пополняются сведениями о фенотипической картине уже описанных вариантов и найденных впервые. Цель: изучить спектр мутаций в гене FBN1 в белорусской выборке пациентов с СМ и оценить диагностическую значимость выявленных генетических вариантов. Методы. В исследование включен 21 неродственный пациент с СМ. Для верификации диагноза всем пациентам методом NGS проведено секвенирование кодирующей последовательности. Найденные замены подтверждались прямым секвенированием по Сэнгеру. Патогенность выявленных вариантов оценивалась согласно базам данных (ClinVar, HGMD) и критериям Американского сообщества медицинских генетиков (ACMG, 2015 г.). Результаты. У 10 из 21 (47,62 %) пациентов с клиническим диагнозом СМ выявлено 10 редких вариантов нуклеотидной последовательности гена FBN1, три (30%) из которых обнаружены впервые. Интерпретация патогенности в базах данных ClinVar и HGMD существенно различалась. Только один из 7 вариантов, описанных ранее, указан как патогенный в обеих базах (ClinVar, HGMD), 3 варианта имели неопределенную клиническую значимость (VUS, III класс) в базе ClinVar, при этом один из них (p.Cys1159Tyr) описан как диагностически значимый в HGMD (DM, IV–V класс). Вариант р.Asp2291Gly, представленный в ClinVar как VUS, и замена p.Cys2674Tyr, патогенная в ClinVar, отсутствовали в базе HGMD, а варианта p.Cys1956Arg, диагностически значимого в базе HGMD, не было в ClinVar. Описанный же ранее вариант p.Cys2617TrpfsTer65 на данный момент не зарегистрирован ни в одной из баз. Вариант p.Thr1020Ala был определен как VUS в обеих базах и характеризовался наиболее благоприятным течением заболевания. Три варианта обнаружены впервые и являются патогенными согласно критериям ACMG: c.3838G>C (p.Asp1280His), c.7694G>C (p.Cys2565Ser), c.7849T>C (p.Cys2617Arg). В работе приведено подробное описание фенотипического проявления новых мутаций. Большинство патогенных мутаций находились в экзонах 62 и 64. Заключение. Обнаружено 10 редких вариантов в гене FBN1, 9 из которых являлись патогенными согласно критериям ACMG (2015 г.). Для 4 (40%) вариантов данные в базах ClinVar и HGMD различались. Полученные данные указывают на необходимость уточнения интерпретации патогенности некоторых вариантов в гене FBN1. Использование данных двух баз позволило подтвердить патогенный статус для существенно большего количества вариантов. Три новых миссенс-варианта были патогенными по предикторам in silico и приводили к тяжелому течению СМ, что указывает на их диагностическую значимость. Background. Marfan syndrome (MS) is one of the frequently occurring diseases of the connective tissue dysplasia group, with a population prevalence of 2-3 cases per 10000 people. The life expectancy of patients is limited by lesions of the cardiovascular system. Diagnosis is based on the Ghent criteria (2010), in which the detection of a pathogenic mutation in the FBN1 gene is important. The gene, located on the 15th chromosome and containing 66 exons (65 of them coding), currently has more than 3000 nucleotide variants. Databases of pathogenic mutations are constantly updated with information about phenotypic manifestation of variants already described and those found for the first time. Aim: to study the spectrum of mutations in the FBN1 gene in the Belarusian sample of patients with MS and to evaluate the diagnostic significance of the identified genetic variants. Methods. The study included 21 unrelated patients with CM. To verify the diagnosis, sequencing of coding sequence was performed in all patients by NGS method. The found substitutions were confirmed by direct Sanger sequencing. The pathogenicity of the identified variants was assessed according to databases (ClinVar, HGMD) and criteria of the American Community of Medical Geneticists (ACMG, 2015). Results. In 10 out of 21 (47.62 %) patients with clinical diagnosis of Marfan syndrome 10 rare variants of nucleotide sequence of FBN1 gene were detected, three (30 %) of which were detected for the first time. The interpretation of pathogenicity in the ClinVar and HGMD databases differed significantly. Only one of the 7 previously described variants is listed as a pathogenic mutation in both databases (ClinVar, HGMD), 3 variants had uncertain clinical significance (VUS, class III) in the ClinVar database, with one of them (p.Cys1159Tyr) described as diagnostically significant in HGMD (DM, class IV-V). The variant p.Asp2291Gly, represented as VUS in ClinVar, and the replacement p.Cys2674Tyr, pathogenic in ClinVar, were absent in the HGMD database, and the variant p.Cys1956Arg, diagnostically significant in the HGMD database, was not present in ClinVar. The previously described variant p.Cys2617TrpfsTer65 is currently not registered in either database. The variant p.Thr1020Ala was identified as VUS in both bases and was characterized by the most favorable course of the disease. Three variants were detected for the first time and are pathogenic according to ACMG criteria: c.3838G>C (p.Asp1280His), c.7694G>C (p.Cys2565Ser), c.7849T>C (p.Cys2617Arg). The paper provides a detailed description of the phenotypic manifestation of the new mutations. Most of the pathogenic mutations were located in exons 62 and 64. Conclusions. Ten rare variants in the FBN1 gene were detected, 9 of which were pathogenic according to the ACMG criteria (2015). For 4 (40%) variants the data in ClinVar and HGMD databases differed. The data obtained indicate the need to clarify the interpretation of pathogenicity of some variants in the FBN1 gene. The use of data from the two databases allowed us to confirm the pathogenic status for a significantly larger number of variants. Three new missense variants were pathogenic by in silico predictors and led to a severe course of MS, indicating their diagnostic significance.

Aim. To analyze the correlation between genotype and phenotype in patients with biventricular arrhythmogenic right ventricular cardiomyopathy (ARVC).Methods. The clinical phenotype of 9 unrelated probands (89 % men, median age 35 [34; 37]) with biventricular ARVC were observed. The clinical and instrumental examination included a 12-lead ECG, 24-hour Holter ECG monitoring, transthoracic echocardiography and cardiac magnetic resonance imaging with late gadolinium enhancement. Biventricular variant of ARVC was diagnosed according to the 2020 Padua criteria for both right and left ventricles involvement. High-throughput sequencing was utilized to search for mutations in genes linked to the onset of cardiomyopathies and other inherited rhythm disorders. Statistical analysis procedures were performed using the STATISTICA-12 program.Results. In all patients with biventricular ARVC, according to late gadolinium enchansment magnetic resonance imaging, left ventricular involvement of varying degrees was detected, characterized by fibrous or fibrofatty infiltration of the myocardium, as well as regional or global systolic dysfunction. Genotyping in 9 patients with biventricular ARVC revealed 10 variants of the nucleotide sequence of III-V classes of pathogenicity according to the criteria of ACMG (2015) in 4 genes associated with ARVC (PKP2, DSP, DSC2, DSG2). Of these, 7 variants belonged to classes IV and V (PKP2 - 4 mutations, DSP - 2 mutations, DSG2 - 1 mutation); 3 nucleotide substitutions were variants with uncertain significance (VUS, class III) - 2 in DSC2 gene and 1 in DSP gene. A combination of nucleotide variants in two genes (DSP and DSC2) was detected in 1 patient. The findings highlight that mutations in DSP gene were associated with more severe systolic dysfunction and left ventricle dilation compared to carriers of mutations in PKP2 gene. In patients with variants of class III pathogenicity in DSC2 gene the most adverse clinical course of the disease was observed with the early onset of the first sustained ventricular tachycardia and the development of severe dysfunction and dilation of both ventricles requiring heart transplantation in comparison with carriers of mutations in other genes.Conclusion. The results obtained in a cohort of patients with biventricular ARVC demonstrate a specific correlation between genotype and clinical course and disease severity as well.

AIM: of the study was to evaluate the clinical and genetic characteristics, including the development of adverse events and outcomes in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). MATERIALS AND METHODS: The clinical phenotype of eight patients with CPVT, two of whom were relatives of probands, was observed over 4 years. The clinical and instrumental study included ECG-12, 24-hour Holter ECG monitoring, genealogical history collection and family history of sudden cardiac death (SCD), transthoracic echocardiography and cardiac magnetic resonance imaging to detect structural myocardial changes, electrophysiologic study according to indications, and ICD monitoring. High-throughput sequencing (NGS) was utilized to search for mutations in genes linked to the onset of channelopathies and other inherited rhythm disorders. RESULTS: In 8 patients, nucleotide variants of pathogenicity classes III-V were identified according to the ACMG (2015) criteria in the RYR2 gene associated with CPVT. Pathogenic (IV-V class) and likely pathogenic (IV class) mutations in the RYR2 gene were found in 6 (75%) probands, variants with uncertain clinical significance (VUS, class III) were found in 2 patients. At the time of diagnosis, transient QTc interval prolongation of more than 480 ms was detected in 4 (50%) patients; bradycardia less than 54 beats/min — in 2 (25%) patients, sequences of supraventricular tachycardia and ventricular tachyarrhythmia — in 2 (25%) patients. The most severe form of the disease with marked clinical manifestations and an episode of clinical death with subsequent resuscitation, as well as a transient QTc interval prolongation exceeding 500 ms was observed in patients with mutations c.11814C A (p.Ser3938Arg, rs794728704); c.463G A (p.Gly155Arg) and c.14876G A (p.Arg4959Gln, rs794728811) in the RYR2 gene. Three (37.5%) patients underwent ICD implantation; one for primary SCD prevention and two for secondary prevention. CONCLUSION: In this study, the spectrum of clinical manifestations in patients with genetically confirmed CPVT was examined. The findings highlight transient QTc interval extensions, significant sinus bradycardia, and sequences of supraventricular tachyarrhythmias, which can escalate into life-threatening ventricular tachyarrhythmias in CPVT patients.

This article describes clinical observation over a patient with a biventricular form of arrhythmogenic cardiomyopathy associated with a mutation in DSG2 gene. The morphological realization of this mutation is associated with fibrous-fat replacement of the myocardium of both ventricles of the heart, which is clinically manifested by the development of life-threatening ventricular arrhythmias and a high risk of biventricular heart failure with a tendency to a progressive decrease in myocardial contractility. The affect on young people of working age, hereditary determinism and an unfavorable prognosis of survival actualizes the importance of diagnostic alertness in the examination of young patients with a clinical picture including ventricular arrhythmias, presyncope, syncope conditions and sudden cardiac death. The main issues of diagnosis, criteria for diagnosis in accordance with the Padua criteria (2020), current principles of treatment and prevention of sudden cardiac death are considered.

AIM: The study was to evaluate the clinical and genetic characteristics of inherited arrhythmias in patients who survived unexplained cardiac arrest. MATERIALS AND METHODS: 20 patients (10 male and 10 female) aged 15 to 55 years (median age 36 [28; 44] years) with documented VT/VF on ECG were observed for 3 years. The clinical and instrumental study included registration of 12-lead ECG, 24-hour Holter ECG, genealogical history collection and family history of sudden cardiac death with ECG assessment of all family members, transthoracic echocardiography, 2D Speckle Tracking echocardiography and cardiac magnetic resonance imaging to exclude structural myocardial changes. High-throughput sequencing (NGS) was utilized to search for mutations in genes linked to the onset of channelopathies and other inherited rhythm disorders. RESULTS: In 4 (20 %) of the 20 probands included in the study, likely pathogenic variants were identified (pathogenicity class IV), and in 7 (35 %) patients, variants with unknown clinical significance (pathogenicity class III) in 10 genes associated with channelopathies (KCNQ1, KCNH2, SCN5A, AKAP9, ANK2, SCN10А, RYR2) and cardiomyopathies (MYH7, JPH2, RBM20). Several genetic variants were found in 3 cases. No significant genetic changes were detected in 9 (45 %) probands. The clinical diagnosis was established during the follow-up period and was verified due to the genetic testing in 5 (25 %) patients. From their ECGs, a prolonged QTc 460 ms was found in 1 patient, Brugada pattern in 2 individuals, and a shortening of QTc up to 323 ms in 1 proband. Subclinical structural changes associated with cardiomyopathies were revealed in 2 patients. In 15 (75 %) patients, it was unfeasible to establish a distinct clinical phenotype. In 6 (30 %) probands, the diagnosis was clarified due to detected genetic variants. CONCLUSION: Clinical manifestations and diverse genetic variants have been studied in patients who have survived unexplained cardiac arrest. In the course of genotyping patients who suffered unexplained cardiac arrest, genetic changes associated with LQTS were detected in 30 % of cases, while the QTc in most cases did not exceed 440 ms, which makes it difficult to establish a diagnosis at an early stage before the development of life-threatening arrhythmic events. The data from our study confirm the idea that in patients with idiopathic ventricular fibrillation, who have suffered unexplained cardiac arrest, cardiac channelopathy or subclinical manifestations of cardiomyopathy are commonly the cause. This phenomenon imposes a need for genetic testing in this category of patients.

Using NGS, the coding sequence of the TTN gene was sequenced in patients with left ventricular non-compaction cardiomyopathy (LVNC, 44 individuals) and hypertrophic cardiomyopathy (HCM, 74 individuals), as well as in the control (194 individuals), and 9 nucleotide variants leading to truncated titin (TTNtv) and 372 missense variants were identified. A comparative analysis of the genetic variability of titin between the groups of patients with LVNC and HCM and the control sample was carried out in terms of the type of mutations and their localization in the exons of genes, as well as in the sarcomeric and functional domains of the protein. The role of TTNtv in the development of LVNC was confirmed, and the significance of additional variants in the same gene or in other genes associated with various cardiomyopathies for the phenotypic implementation of TTNtv was demonstrated. 75% of patients with TTNtv had a dilated LVNC phenotype. Missense substitutions in the TTN gene were found both among the patients with LVNC and HCM, and in people in the control sample, which indirectly confirms that most missense variants in this gene are benign. The paper identifies and lists highly mutable and conserved exons of the TTN gene and also presents a list of missense mutations with possible clinical significance in relation to the structural pathology of the myocardium, including new variants. It was shown that the majority of pathogenic and potentially significant mutations were located in the A-zone of the sarcomere. In all the groups, about 30–50% of new variants were identified. Probably, many of them are neutral and are of exclusively population interest.

Aim. To assess the prevalence of the left ventricle involvement and the features of the biventricular phenotype of arrhythmogenic cardiomyopathy in patients with pathogenic mutations in the PKP2 and DSP genes. Material and methods. Three unrelated probands underwent a comprehensive molecular-genetic, clinical and instrumental examination, which included a 12-lead ECG, 24-hour ECG monitoring, transthoracic echocardiography, and cardiac magnetic resonance imaging with late gadolinium enhancement. Results. The results of our clinical observations showed that in three studied patients with arrhythmogenic cardiomyopathy left ventricle involvement of various degree was found. The left ventricle damage was characterized by fibrous or fibro-fatty infiltration of the myocardium, as well as regional or global systolic dysfunction of different severity. The patients had pathogenic mutations c.1912C > T (p.Gln638*, rs397517012, rs397517012); c.1237C > T (p.Arg413*, rs372827156) in the PKP2 gene and a new probably pathogenic variant in the form of a c.3494delA deletion in the DSP gene. It was found that the mutation in the DSP gene was associated with a more pronounced systolic dysfunction and a greater percentage of fibrous replacement of the left ventricular myocardium compared with carriers of mutations in the PKP2 gene. All patients had life-threatening ventricular arrhythmias with the need for implantation of a cardioverter-defibrillator. Conclusion. Our clinical observations have shown that in patients with biventricular arrhythmogenic cardiomyopathy, the detection of a mutation in the DSP gene is associated with a more pronounced systolic dysfunction and a higher percentage of fibrous replacement of the left ventricle myocardium compared with carriers of mutations in the PKP2 gene.

Инфекция COVID-19 представляет потенциальные риски для пациентов с каналопатиями. Сочетание многих проаритмогенных факторов, включая гипертермию, стресс, гипоксию, электролитные нарушения, диарею, а также применяемые в настоящее время лекарственные средства (ЛС) для лечения инфекции могут являться потенциальной причиной удлинения интервала QTc и приводить к возникновению угрожающих жизни аритмий. Поэтому пациентам с LQTS следует проявлять особую осторожность и при инфицировании COVID-19 желательна их госпитализация в стационар для адекватного мониторирования интервала QTc. Особые трудности диагностики вызывают пациенты с предрасположенностью к удлинению интервала QT и наличием преходящего или латентного удлинения интервала QTc. Авторы представляют клинический случай 29-летней пациентки, у которой на фоне гипертермии, диареи и рвоты, обусловленных инфекцией COVID-19, появились рецидивирующие пресинкопальные состояния и сердцебиения. Диагноз преходящего LQTS пациентке был установлен на основании эпизодов удлинения QTc до 609 мс при мануальной оценке ХМ ЭКГ на фоне тахикардии более 120 уд/мин. Оценка вероятности LQTS по шкале Шварца составила 4,0 балла. При молекулярно-генетическом исследовании обнаружено сочетание нескольких редких генетических вариантов с неопределенной значимостью в генах KCNE1, HCN4 и ANK2, кодирующих ионные каналы и ассоциированных с каналопатиями и нарушениями сердечного ритма. Комбинация нескольких генетических вариантов могла играть существенную роль как в вариабельности экспрессии фенотипа заболевания, так и в разнообразии ответов на различные провоцирующие факторы, обусловленные инфекцией COVID-19. COVID-19 presents potential risks for patients with channelopathies. A combination of many proarrhythmogenic factors, including hyperthermia, stress, hypoxia, electrolyte disturbances, diarrhea, as well as currently used drugs for the treatment of infection could be a potential cause of prolongation of the QTc interval and lead to life-threatening arrhythmias. Therefore, patients with LQTS should exercise special caution and when infected with COVID-19, their hospitalization in a hospital is desirable for adequate monitoring of the QTc interval. Particular diagnostic difficulties are caused by patients with a predisposition to prolongation of the QT interval and the presence of transient or latent prolongation of the QTc interval. The authors present a clinical case of a 29-year-old patient who, against the background of hyperthermia, diarrhea and vomiting caused by COVID-19, had recurrent presyncopal episodes and palpitations. The diagnosis of transient LQTS in the patient was established on the basis of episodes of QTc prolongation up to 609 ms with manual assessment of ECG monitor against a background of tachycardia of more than 120 bpm. The LQTS probability score on the Schwartz scale was 4.0 points. A molecular genetic study revealed a combination of several rare genetic variants with uncertain significance in the genes KCNE1, HCN4 and ANK2 encoding ion channels and associated with channelopathy and cardiac arrhythmias. The combination of several genetic variants could play a significant role both in the variability of the expression of the disease phenotype and in the diversity of responses to various provoking factors caused by COVID-19.

The aim of the study is to evaluate clinical characteristics, including adverse events and outcomes, in patients with various genetic types of long QT syndrome (LQTS).Material and methods. We examined 24 patients with a clinical diagnosis of LQTS, observed in the for 5 years. The clinical and instrumental study included registration of electrocardiography (ECG), Holter monitoring, collection of a genealogical history with an ECG assessment of all family members and identification of cases of sudden cardiac death (SCD) in the family or the presence of a family form of the disease, echocardiography and cardiac magnetic resonance imaging to exclude structural changes in the myocardium. The search for mutations in the coding sequences of genes associated with the development of channelopathy and other hereditary heart rhythm disorders was carried out by next generation sequencing (NGS).Results. Mutations in 4 genes associated with LQTS (KCNQ1, KCNH2, CACNA1C, ANK2) were detected in 18 out of 24 (75.0%) patients. Mutations in the KCNQ1, KCNH2 and CACNA1C genes were detected in 14 (58.0%) patients. In 4 out of 24 (17%) patients, two or more variants of clinical significance (VUS) were detected in the genes associated with LQTS and hereditary arrhythmias, 6 patients had no genetic changes. The most severe form of the disease with pronounced clinical manifestations and episodes of clinical death with subsequent resuscitation measures, as well as a significant increase in the QTc interval exceeding 500 ms, was observed in patients with LQT2 and multiple mutations. Implantation of a cardioverter-defibrillator (CD) was required in 14 (58.3%) patients, including 11 (78.56%) - for secondary prevention of SCD and 3 (21.4%) - for primary prevention.Conclusion. A comparative analysis between different genetic types of LQTS (LQT1; LQT2; patients with multiple VUS) showed that in patients with LQT1 syndrome, despite the early manifestation of the disease and the presence of syncopal conditions, life-threatening arrhythmias, SCD and the frequency of CD implantation were significantly less often recorded than in other LQTS. The most severe form of the disease with pronounced clinical manifestations, episodes of clinical death with subsequent resuscitation and CD implantation was observed both in the group of probands with LQT2 and in patients with several nucleotide variants (VUS), one of which was in the CACNA1C or ANK2 genes.

The aim of the study is to evaluate clinical characteristics, including adverse events and outcomes, in patients with various genetic types of long QT syndrome (LQTS). Material and methods. We examined 24 patients with a clinical diagnosis of LQTS, observed in the for 5 years. The clinical and instrumental study included registration of electrocardiography (ECG), Holter monitoring, collection of a genealogical history with an ECG assessment of all family members and identification of cases of sudden cardiac death (SCD) in the family or the presence of a family form of the disease, echocardiography and cardiac magnetic resonance imaging to exclude structural changes in the myocardium. The search for mutations in the coding sequences of genes associated with the development of channelopathy and other hereditary heart rhythm disorders was carried out by next generation sequencing (NGS). Results. Mutations in 4 genes associated with LQTS (KCNQ1, KCNH2, CACNA1C, ANK2) were detected in 18 out of 24 (75.0%) patients. Mutations in the KCNQ1, KCNH2 and CACNA1C genes were detected in 14 (58.0%) patients. In 4 out of 24 (17%) patients, two or more variants of clinical significance (VUS) were detected in the genes associated with LQTS and hereditary arrhythmias, 6 patients had no genetic changes. The most severe form of the disease with pronounced clinical manifestations and episodes of clinical death with subsequent resuscitation measures, as well as a significant increase in the QTc interval exceeding 500 ms, was observed in patients with LQT2 and multiple mutations. Implantation of a cardioverter-defibrillator (CD) was required in 14 (58.3%) patients, including 11 (78.56%) for secondary prevention of SCD and 3 (21.4%) for primary prevention. Conclusion. A comparative analysis between different genetic types of LQTS (LQT1; LQT2; patients with multiple VUS) showed that in patients with LQT1 syndrome, despite the early manifestation of the disease and the presence of syncopal conditions, life-threatening arrhythmias, SCD and the frequency of CD implantation were significantly less often recorded than in other LQTS. The most severe form of the disease with pronounced clinical manifestations, episodes of clinical death with subsequent resuscitation and CD implantation was observed both in the group of probands with LQT2 and in patients with several nucleotide variants (VUS), one of which was in the CACNA1C or ANK2 genes.

Катехоламинергическая полиморфная желудочковая тахикардия (КПЖТ) и синдром удлиненного интервала QT (LQTS) являются двумя различными каналопатиями, проявляющимися преимущественно у молодых пациентов при структурно нормальном сердце сходной клинической картиной, но с разным клиническим течением.Авторы представляют клинический случай атипичной КПЖТ у родственных пациентов, характеризующейся транзиторным удлинением интервала QT без связи с физической нагрузкой. У 8-летнего пробанда с рецидивирующими синкопальными состояниями на фоне полиморфной желудочковой тахикардии с транзиторным удлинением интервала QT развилась фибрилляция желудочков (ФЖ) и внезапная сердечная смерть (ВСС). У его 32-летней матери также наблюдались синкопальные состояния, эпизоды полиморфной ЖТ с транзиторным удлинением интервала QT и вероятностью наличия LQTS по шкале Шварца 5,0 балла, что позволило установить диагноз LQTS. Пациентке был имплантирован ИКД с целью первичной профилактики ВСС. При молекулярно-генетическом исследовании у матери и сына обнаружена вероятно патогенная мутация в гене RYR2, описанная ранее у пациентов с КПЖТ. Таким образом, под маской транзиторного удлинения интервала QT может скрываться диагноз КПЖТ, поэтому требуется внимательное рассмотрение клинических данных и обязательное генотипирование пациента. Хотя лечение обеих каналопатий одинаковое, клинические исходы различны, так как КПЖТ проявляется более злокачественным клиническим течением. Catecholaminergic polymorphic ventricular tachycardia (CPVT) and long QT syndrome (LQTS) are two different channelopathies, manifested mainly in young patients with a structurally normal heart with similar clinical manifestations, but with a different clinical course.The authors present a clinical case of atypical CPVT in related patients characterized by transient prolongation of the QT interval without connection with physical exertion. An 8-year-old proband with recurrent syncopal conditions against the background of polymorphic ventricular tachycardia with transient prolongation of the QT interval developed ventricular fibrillation (VF) and sudden cardiac death (SCD). His 32-year- old mother also had syncopal episodes, episodes of polymorphic VT with transient prolongation of the QT interval and a probability of having LQTS on the Schwartz scale of 5.0 points, which allowed the diagnosis of LQTS to be established. The patient was implanted with an ICD for the purpose of primary prevention of SCD. The genetic study of the mother and son revealed a likely pathogenic mutation in the RYR2 gene, previously described in patients with CPVT.Thus, under the mask of a transient prolongation of the QT interval, the diagnosis of CPVT may be hidden, therefore, careful consideration of clinical data and mandatory genotyping of the patient is required. Although the treatment of both channelopathies is the same, the clinical outcomes are different and CPVT is manifested by a more malignant clinical course.

Aim: evaluate clinical and structural-functional characteristics, including adverse events and outcomes, in patients with noncompact cardiomyopathy (NCM) with various genetic variants. Material and Methods. 51 unrelated patients with NCM were examined (mean age 37 [28; 47]; men (54.9%), women (45.1%)), observed for 7 to 211 months (in average 38 months). Clinical and instrumental examination included checkup, collection of individual and family history, ECG-12 registration, 24-hour Holter ECG monitoring, echocardiography, magnetic resonance imaging (MRI) of the heart with late contrast enhancement. The search for mutations in the coding sequences of 174 genes associated with cardiovascular pathology was carried out by high-throughput sequencing (NGS). Results and discussion. In 24 of 51 (47.1%) patients, 27 mutations of pathogenicity classes IV and V were detected, while in 21 (41.2%) patients, mutations were in the genes of sarcomeric proteins, of which 37.5% were in the MYBPC3 gene, 25.0% in the MYH7 gene, and in the TTN gene, leading to a shortened protein ( TTNtv ) – 33.3%, there is a mutation in the ACTC1 – 1 gene (4.2%). In 5.9% of patients, mutations were detected in genes encoding structural proteins and ion channel subunits. Two or more genetic variants were found in 10 out of 24 (41.7%) patients. No significant genetic variants were identified in 14 (27.4%) patients. Patients with mutations in the TTNtv gene were associated with severe systolic dysfunction, dilation of the left ventricle. Carriers of mutations in the MYBPC3 gene and several genetic variants were more likely to have adverse events and outcomes: progression of chronic heart failure (CHF), ventricular tachyarrhythmias, sudden cardiac death (SCD) with successful resuscitation, mortality. Patients with mutations in the MYH7 gene had no adverse outcomes. Conclusion . Comparative analysis showed that patients with NCM had the most severe form of the disease with significant clinical manifestations, episodes of clinical death with subsequent resuscitation and cardioverter defibrillator implantation in probands with mutations in TTNtv gene, mutations in the MYBPC3 gene or multiple genetic variants.

A clinical case of a patient with non-compaction cardiomyopathy, early development of life-threatening arrhythmias and conduction disorders, myopathic syndrome and mutations in the LMNA and KCNH2 genes is presented. The issues of diagnostics based on imaging technologies, complex differential diagnostics of non-compaction cardiomyopathy and dilated cardiomyopathy, as well as the basic principles of treatment are discussed. We also present the main provisions of European and American experts on the concept of isolation of lamina-associated cardiomyopathies for mandatory molecular genetic testing and, if identified, early implantation of ICD for the prevention of SCD.

The investigation of the pathogenesis of chronic rhinosinusitis in patients with cystic fibrosis (CF) and analysis of molecular biomarkers can promote the development of tailored approaches to its treatment and prevention. Objective. To analyze associations between sinonasal polyposis and genetic polymorphisms of the xenobiotic metabolizing enzymes (XMEs) in CF patients. Patients and methods. We performed a retrospective comparative analysis of 145 CF patients from the Russian Federation (RF) and 82 patients from the Republic of Belarus (RB). Patients provided blood samples that were later used for DNA extraction; clinical information was collected for all study participants. The diagnosis was based on the guidelines of the European and Russian Consensus. This was a case-control study. The XME gene polymorphisms were assessed using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) or amplified fragment length polymorphism (AFLP) analysis with special primers. The following genes and polymorphic variants were chosen for the study: phase I (CYP2C9*3 (rs1057910; c.1075A>C; I359L), CYP2C9*2 (rs1799853; c.430C>T; R144C), CYP2C19*2 (rs4244285; c.681G>A), CYP2C19*3 (rs4986893; c.636G>A; W212X), CYP2D6*4 (rs3892097; c.1846G>A), CYP3A4*3 (rs4986910; M445T; c.1334T>C), CYP3A4*1B (rs2740574; c.-392C>T); phase II (deletions in GSTT1 and GSTM1; GSTP1 (c.313A>G); GCLC (TNR(GAG), c.-129C>T); GCLM (c.-588C>T); NAT2 (c.191G>A, c.282C>T, c.341T>C, c.434A>C, c.481C>T, c.590G>A, c.803A>G, c.845A>C, c.857G>A)). Results. Mean patient age was 12.69 ± 6.9 years (5.03–40.36) and did not vary between the RF and RB patients. The male to female ratio was 0.52:0.48 (118:109). Nasal polyposis was diagnosed in 61 patients (26.9%), while 166 children (73.1%) had no nasal polyps. We found that patients with chronic rhinosinusitis and nasal polyps were more likely to have ‘severe’ CFTR genotypes: 95.6% vs 4.4% of patients with a ‘mild’ genotype (р = 0.05). We observed no significant associations between nasal polyposis and analyzed XME gene polymorphisms, as well as glutathione metabolic genes. Conclusion. We found no associations between nasal polyposis and XME gene polymorphisms (phase 1 and 2), which suggests the need for further research aimed to identify other molecular mechanisms underlying the development of nasal polyps in CF patients. Key words: sinonasal polyposis, chronic rhinosinusitis, xenobiotic biotransformation enzymes, cystic fibrosis, glutathione, inflammation

The TBX5 gene encodes the T-box transcription factor 5 (Tbx5) involved in the regulation of developmental processes in both vertebrates and invertebrates. Mutations in this gene cause rare monogenic Holt–Oram syndrome (HOS) characterized by skeletal anomalies of the upper limbs, a congenital heart defect, and/or сardiac сonduction system diseases. Next generation sequencing (NGS) made it possible to detect a new nucleotide variant c.713G>C (p.Gly238Ala) in the TBX5 gene in a patient with a mild Holt–Oram syndrome phenotype (thoracic spine deformity (scoliosis) and scapula dysplasia and showing signs of mitral and triсuspid valve insufficiency with first- and second-degree regurgitation and atrial septal thinning) and life-threatening tachyarrhythmias that required a cardioverter-defibrillator implantation (CDI). The mutation is localized in the “hot spot” of the TBX5 gene. Evaluation of its pathogenicity by in silico analysis showed that the c.713G>C nucleotide substitution can lead to changes in the protein structure and/or its function. Non-sustained ventricular tachycardia/ventricular fibrillation, which is not characteristic of HOS, could have resulted from two additional rare substitutions (MAF < 0.01%): p.Val3634Asp, rs66785829 in the ANK2 gene and p.Arg1193Gln, rs41261344 in the SCN5A gene. Mutations in these genes affect the voltage-gated sodium channel functioning and cause hereditary arrhythmia.

Type of funding sources: None. Purpose. To evaluate the genotype-phenotype association in Belarusian patients with non-compaction cardiomyopathy (NCCM) and clinically significant ventricular arrhythmias. Methods. The study included 170 unrelated pts with NCCM prospectively observed in the RSPC "Cardiology", who underwent 24-hour Holter ECG monitoring for 12 months after entering the study. The median follow-up was 36 months [6; 152,0]. The median age of pts was 42 [18; 69] years, men – 63,2%. The arrhythmic phenotype of NCСM was diagnosed by the presence of unexplained syncope; nonsustained ventricular tachycardia, defined as ≥3 consecutive ventricular contractions lasting <30 seconds with a frequency of ≥120 bpm; the presence of ≥ 500 ventricular premature beats (VPB) per day. The diagnosis of NCCM was established on the basis of the following criteria: 1) Echocardiography of the R. Jenni criteria; 2) CMR of the S. Petersen and A. Jaquier criteria. The mutations search in the coding sequences of 174 genes was performed in 30 unrelated pts with NCCM using next generation sequencing (NGS). Results. In 76 out of 170 (44,7%) pts, clinically significant arrhythmias were the leading manifestation of the disease. Nonsustained VT was recorded in 54 (71,1%) pts, sustained VT – in 15 (19,7%) pts, VPB more than 500 per day – in 50 (65,8%), chronic AF with episodes of nonsustained VT was noted in 34 (44,7%) pts. During the follow-up period (median follow-up of 36 months), devices (ICD/CRT-D) were implanted in 15 (19,7%) pts, appropriate shocks were observed in two of them; three pts died, among which SCD occurred in one patient with CRT-D therapy, which was ineffective in stopping sustained VT. NGS sequencing revealed 40 changes in the nucleotide sequence (5 pathogenic mutations, 30 variants with uncertain significance (VUS), 5 new substitutions) in 27 genes in 26 (86,7%) probands. The proportion of mutations in sarcomeric proteins genes was 26,9%, and in ion channel proteins genes was 23,1%. Nucleotide changes in genes encoding structural proteins accounted for 11,5%. In 38,5% of cases, not one, but two or more rare mutations were detected, and in 30,8% – amino acid replacements were found in proteins of different functional classes. Conclusions. The frequency of multiple mutations was higher (38,5%) in the group of pts with the arrhythmic NCCM phenotype. In the group of pts with implantable devices (ICD/CRT-D), mutations in the genes of sarcomeric proteins were observed more often. The genetic characteristics of pts, along with their clinical characteristics, are markers of a high risk of developing life-threatening arrhythmias and can be additionally used for predicting adverse events in pts with NCCM, as well as for early diagnosis of the disease in their relatives.

Синдром Холта – Орама (HOS) – генетическое заболевание, вызванное мутацией в гене TBX5, хромосома 12q24, который регулирует широкий спектр процессов развития сердца, сосудов и конечностей. В настоящей работе представлен клинический случай синдрома HOS у 42-летней пациентки с мягким фенотипом заболевания и жизнеугрожающими нарушениями ритма (устойчивая желудочковая тахикардия / фибрилляция желудочков), по поводу которых был имплантирован кардиовертер-дефибриллятор (ИКД). При генетическом исследовании были выявлены мутация c.713G>C (p.Gly238Ala) в гене TBX5, указывающая на наличие у пациентки синдрома HOS, и две редкие замены c.10901T>A (p.Val3634Asp), rs66785829 в гене ANK2, отвечающем за синтез анкирина-В, c.35758G>A (p.Arg1193Gln), rs41261344 в гене SCN5A, кодирующем субъединицу потенциал-зависимого натриевого канала Nav1.5, ассоциированные с развитием наследственных аритмий. Обсуждены вопросы диагностики и стратегии лечения. Holt – Oram syndrome (HOS) is a genetic disease caused bya mutation in theTBX5 gene, chromosome 12q24, which regulates a wide range of heart, vascular, and limb development processes. This paper presents a clinical case of HOS syndrome in a 42-year-old patient with a mild disease phenotype and life-threatening rhythm disorders (sustained ventricular tachycardia/ventricular fibrillation), for which a cardioverter defibrillator (ICD) was implanted. The genetic study revealed a mutation c.713G>C (p.Gly238Ala) in the TBX5 gene, indicating the presence of HOS syndrome in the patient, and two rare substitutions c.10901T>A (p.Val3634Asp), rs66785829 in the ANK2 gene responsible for ankyrin-B synthesis; c.35758G>A (p.Arg1193Gln), rs41261344 in the SCN5A gene encoding the Nav1.5 potential dependent sodium channel subunit associated with the development of hereditary arrhythmias.The issues of diagnostics and treatment were discussed.