Spectrum of mutations and their phenotypic manifestations in children and adults with long QT syndrome

Aim. To determine the spectrum of mutations in the genes responsible for the long QT syndrome (LQTS) and study their phenotypic manifestations in patients with LQTS in different age groups.Materials and methods. The study included 35 unrelated probands with a clinical diagnosis of LQTS: 23 adults (8 men) and 12 children (9 boys). There were following clinical features: syncope — 54%, positive family history for SCD — 29%, implanted cardioverter defibrillator (ICD) — 46%. All participants underwent 12-lead electrocardiography (ECG), 24-hour Holter monitoring, genealogical analysis, echocardiography and cardiac MRI. The genetic study was performed by nextgeneration sequencing (NGS) using the MiSeq system (Illumina). The quantitative comparison of two unrelated groups was carried out using the nonparametric MannWhitney U-test. The differences were considered significant at p<0,05.Results. In the examined group of 35 probands, 23 genetic variants of pathogenicity class IV and V (hereinafter referred to as) were identified. The molecular genetic variant of the disease was verified in 66% of probands. At the same time, the detection of mutations in the group with early manifestation (children) was significantly higher: 83% (10 out of 12 children) vs 57% in adults (13 out of 23). Rare genetic variants of uncertain significance (VUS, class III pathogenicity) were detected in 4 probands (11%). In the groups of children and adults with LQT1, LQT2 and LQT3, the sex distribution deviated from the 1:1 ratio. Among children, two-thirds were boys, among adults — the same proportion was represented by women. Disease manifestation time, QTc duration and adverse events risk depended on the genetic type of LQTS, intragenic localization of mutations and sex. In children, all 4 missense mutations in the KCNQ1 gene were located in transmembrane domain, and in adults, 4 mutations were in the transmembrane domain and three — in the C-terminal domain of the protein. LQT1 in boys was characterized by early manifestation, while QTc did not exceed 500 ms and there were no adverse outcomes. Two women out of 7 adults with LQT1 with mutations in the transmembrane domain had na ICD (QTc >520 ms). All patients with LQT2 (4 children, 4 adults) had QTc >500 ms. At the same time, 2 children and 3 women had an ICD. LQT3 was diagnosed only in the children subgroup (2 boys, with QTc of 510 ms and QTc of 610 ms); one of them died suddenly despite beta-blocker therapy. Four adult patients, carriers of class III pathogenicity variants, had QTc <500 ms and delayed disease manifestation (after 30 years). Three of them had episodes of clinical death with subsequent resuscitation and implantation of cardioverter defibrillator.Conclusion. The average diagnostic efficiency of mutation identification using NGS in patients with clinically manifest LQTS was 66%. At the same time, mutations were more common in the children’s group. In genotype-positive probands, the risk of adverse outcomes correlated with sex, age and the genetic variant of disease. The greatest number of adverse outcomes was observed in carriers of mutations in both KCNH2 (LQT2) and SCN5A (LQT3) genes. Variants with unknown clinical significance were identified in 4 probands (11%), which potentially allowed to confirm the diagnosis after functional tests

Клинико-генетическая и микробиологическая характеристика больных муковисцидозом, проживающих в Московском регионе и Республике Беларусь

The aim of this study was a comparative analysis of course and treatment of cystic fibrosis (CF) in patients living at Moscow Region or at Republic of Belarus’. Methods. This was a comparative analysis of CF patients living at Moscow region (n = 197) or at Republic of Belarus’ (n = 110). The following clinical data were evaluated: sweat chloride test results if available, sputum microflora, nutritional status, complications of CF, and the current treatment. Results. The patient samples did not differ in gender, age, and lung function and had similar rates of F508del and CFTRdele2,3 mutations and Pseudomonas aeruginosa infection. Similar methods were used in both groups to confirm the diagnosis. The groups differed significantly in prevalence of Staphylococcus aureus, Burkholderia cepacia complex, and non-tuberculosis mycobacteria infections. Adult patients living at Moscow Region have lower forced expiratory volume for 1 sec compared to those living at Republic of Belarus’. CF patients younger 18 years of age who lived at Moscow Region had higher body mass index that those living at Republic of Belarus’. CF patients living at Republic of Belarus’ had hepatic cirrhosis and nasal polyps more often that those living at Moscow Region. Conclusion. CF patients living at Moscow Region and at Republic of Belarus’ had similar health status. Children and adolescents from those regions did not differ in key parameters predicting life expectancy and quality of life in CF. The groups differed in the prevalence of hepatic cirrhosis and nasal polyps. Modern ambulatory management using novel inhaled mucolytic and antibacterial agents, and regular follow-up every 3 months allow maintaining the lung functional status and P. aeruginosa infection rate close to that of the patients managed with regular in-hospital intravenous antibacterial and steroid therapy. Муковисцидоз (МВ) характеризуется поражением многих органов, но в большинстве случаев доминирует патология респираторного тракта. Общее число больных МВ в течение последнего десятилетия значительно увеличилось, возросли также доля взрослых пациентов и выживаемость, улучшилось качество жизни больных МВ. Целью исследования явился сравнительный анализ показателей течения МВ больных, проживающих в Московском регионе (МР) (Москва и Московская область) и Республике Беларусь (РБ) (Минск и регионы), а также объема медикаментозного лечения. Материалы и методы. Настоящая работа представляет собой сравнительный анализ данных пациентов с МВ, проживающих в МР (n = 197) и РБ (n = 110). Анамнестически оценивались следующие клинические данные: хлориды пота при проведении потового теста, микробный пейзаж, нутритивный статус, осложнения течения МВ, проводимая терапия. Результаты. Выборки обследованных больных МВ (n = 307), проживающих в МВ и РБ, практически не различались по частоте встречаемости мутации F508del и CFTRdele2,3, синегнойной инфекции в группах детей, показателям функции легких, полу и возрасту (до 18 лет). Применялись единые методы диагностики заболевания (потовые тесты, ДНК-диагностика). Различия отмечены по частоте Staphylococcus aureus, Burkholderia cepacia complex, нетуберкулезных микобактерий. Отмечены более низкие показатели функции легких по объему форсированного выдоха за 1-ю секунду среди взрослых, проживающих в МР. У детей моложе 18 лет, проживающих в МР, отмечено более высокое значение индекса массы тела. Цирроз и полипозный риносинусит чаще регистрировались среди жителей РБ. Заключение. У больных МВ, проживающих в МР и РБ, выявлены сходные характеристики здоровья. Различий по показателям, определяющим качество и продолжительность жизни при МВ, у детей и подростков обоих регионов не установлено. Зарегистрированы различия в отношении цирроза печени, полипоза и остеопороза. Применение амбулаторной тактики ведения больных, динамического наблюдения (1 раз в 3 мес.) с использованием современных ингаляционных муколитических и ингаляционных антибактериальных препаратов дает возможность поддерживать функцию легких и частоту Pseudomonas aeruginosa так же, как и при внутривенной антибактериальной и гормональной терапии в условиях стационара

POLYMORPHIC VARIANTS OF GENES CODING SYMPATHOADRENAL SYSTEM INFLUENCE ON PHENOTYPE OF PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY

Aim. To reveal the associations of polymorphic genes variants coding the proteins of sympathoadrenal system (ADRB1 and ADRB2) with clinical phenotype of the disease including age and gender of patients with HCMP.Material and methods. The analysis of clinical-demographic and instrumental data of 275 patients with the diagnosis of HCMP (97 women and 178 men, age 17 to 70 y.o., median age 51 y. and 44 y., resp.) was done. All parameters were assessed at the moment of the patients inclusion. Amplification of polymorphic area of the gene was done by PCR method with consequent restriction analysis.Results. Monofactor analysis revealed that atrial fibrillation (AF) is associated with polymorphism of Arg389Gly gene АDRB1 (p=0,028). Heart failure of the higher FC II-III showed tendency to association with polymorphism Arg389Gly gene АDRB1 (p=0,060). Multifactorial analysis showed that the presence of nonsustained ventricular tachycardia episodes (NVT) more often associated with the patients — carriers of heterozygous GC gene АDRB2 (polymorphism Gln27Glu) (OR 1,76; 1,023,06; 95% CI). AF was more rare in the carriers of heterozygous genotype of GC gene АDRB1 (polymorphism Arg389Gly) (OR 0,39 (0,17-0,82; 95% CI) comparing to the normal genotypes. Heart failure of higher FC II-III more often was found in patients — carriers of GC gene АDRB1 (polymorphism Gln27Glu) (OR 4,31; 1,0829,03; 95% CI).Conclusion. Genotype GC of polymorphism gene АDRB2 (polymorphism Gln27Glu) is the most adverse factor that influence such clinical presentations of HCMP as the higher functional class of heart failure and development of life threatening arrhythmias

Isolated glycogen storage disease of the heart

Isolated glycogen storage disease of the heart (PRKAG2 syndrome) is a form of glycogenosis, which is characterized by left ventricular hypertrophy, similar to the phenotype of hypertrophic cardiomyopathy, associated with pre-excitation of the ventricles and conduction disorders. The disease is caused by mutations in the gene PRKAG2 encoding for the 5’Adenosine Monophosphate-Activated Protein Kinase (AMPK), specifically for its y2 regulatory subunit, inheritance — autosomal dominant. A review of the literature data and clinical observation of two patients from the same family with the mutation c905C>A (p.Arg302Gln) in the PRKAG2 gene associated with WPW syndrome and early development of conduction disorders requiring implantation of a pacemaker are presented. The issues of diagnosis and treatment strategy of the disease were discussed

THE SPECIFICS OF HYPERTROPHIC CARDIOMYOPATHY CLINICAL PRESENTATION IN PATIENTS WITH VARIOUS MUTATIONS OF SARCOMERE GENES

Aim. The assessment of clinical presentation of HCMP in patients having mutations of the sarcomere protein genes.Material and methods. In 11 patients with hypertrophic cardiomyopathy (HCMP) we performed analysis of clinical and instrumental data and search for mutations of coding sequences of the genes ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2 и TPM1 via the sequencing method (next-generation sequencing (NGS).Results. The clinical presentation is described, of HCMP, and the analysis provided of the complications development during the period of follow-up of the patients with genes coding sarcomere proteins: Arg403Trp, Lys847del and Arg1712Trp (gene MYH7); Gln1233Term, Trp1214Arg, Arg502Gln, Arg326Gln and Ser236Gly (gene MYBPC3); Arg58Gln in gene MYL2.Conclusion. The revealed mutations in sarcomere genes in patients with HCMP are associated with early clinical onset of the disease, with worse family anamnesis and development of complications during follow-up

Differences between familial and sporadic dilated cardiomyopathy: ESC EORP Cardiomyopathy & Myocarditis registry

Aims: Dilated cardiomyopathy (DCM) is a complex disease where genetics interplay with extrinsic factors. This study aims to compare the phenotype, management, and outcome of familial DCM (FDCM) and non-familial (sporadic) DCM (SDCM) across Europe. Methods and results: Patients with DCM that were enrolled in the prospective ESC EORP Cardiomyopathy & Myocarditis Registry were included. Baseline characteristics, genetic testing, genetic yield, and outcome were analysed comparing FDCM and SDCM; 1260 adult patients were studied (238 FDCM, 707 SDCM, and 315 not disclosed). Patients with FDCM were younger (P\ua0<\ua00.01), had less severe disease phenotype at presentation (P\ua0<\ua00.02), more favourable baseline cardiovascular risk profiles (P\ua0 64\ua00.007), and less medication use (P\ua0 64\ua00.042). Outcome at 1\ua0year was similar and predicted by NYHA class (HR 0.45; 95% CI [0.25\u20130.81]) and LVEF per % decrease (HR 1.05; 95% CI [1.02\u20131.08]. Throughout Europe, patients with FDCM received more genetic testing (47% vs. 8%, P\ua0<\ua00.01) and had higher genetic yield (55% vs. 22%, P\ua0<\ua00.01). Conclusions: We observed that FDCM and SDCM have significant differences at baseline but similar short-term prognosis. Whether modification of associated cardiovascular risk factors provide opportunities for treatment remains to be investigated. Our results also show a prevalent role of genetics in FDCM and a non-marginal yield in SDCM although genetic testing is largely neglected in SDCM. Limited genetic testing and heterogeneity in panels provides a scaffold for improvement of guideline adherence

Differences between familial and sporadic dilated cardiomyopathy: ESC EORP Cardiomyopathy & Myocarditis registry

Aims: Dilated cardiomyopathy (DCM) is a complex disease where genetics interplay with extrinsic factors. This study aims to compare the phenotype, management, and outcome of familial DCM (FDCM) and non-familial (sporadic) DCM (SDCM) across Europe. Methods and results: Patients with DCM that were enrolled in the prospective ESC EORP Cardiomyopathy & Myocarditis Registry were included. Baseline characteristics, genetic testing, genetic yield, and outcome were analysed comparing FDCM and SDCM; 1260 adult patients were studied (238 FDCM, 707 SDCM, and 315 not disclosed). Patients with FDCM were younger (P < 0.01), had less severe disease phenotype at presentation (P < 0.02), more favourable baseline cardiovascular risk profiles (P ≤ 0.007), and less medication use (P ≤ 0.042). Outcome at 1 year was similar and predicted by NYHA class (HR 0.45; 95% CI [0.25–0.81]) and LVEF per % decrease (HR 1.05; 95% CI [1.02–1.08]. Throughout Europe, patients with FDCM received more genetic testing (47% vs. 8%, P < 0.01) and had higher genetic yield (55% vs. 22%, P < 0.01). Conclusions: We observed that FDCM and SDCM have significant differences at baseline but similar short-term prognosis. Whether modification of associated cardiovascular risk factors provide opportunities for treatment remains to be investigated. Our results also show a prevalent role of genetics in FDCM and a non-marginal yield in SDCM although genetic testing is largely neglected in SDCM. Limited genetic testing and heterogeneity in panels provides a scaffold for improvement of guideline adherence

The Cardiomyopathy Registry of the EURObservational Research Programme of the European Society of Cardiology: Baseline data and contemporary management of adult patients with cardiomyopathies

Aims The Cardiomyopathy Registry of the EURObservational Research Programme is a prospective, observational, and multinational registry of consecutive patients with four cardiomyopathy subtypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). We report the baseline characteristics and management of adults enrolled in the registry. ................................................................................................................................................................................................... Methods and results A total of 3208 patients were enrolled by 69 centres in 18 countries [HCM (n = 1739); DCM (n = 1260); ARVC (n = 143); and RCM (n = 66)]. Differences between cardiomyopathy subtypes (P < 0.001) were observed for age at diagnosis, history of familial disease, history of sustained ventricular arrhythmia, use of magnetic resonance imaging or genetic testing, and implantation of defibrillators. When compared with probands, relatives had a lower age at diagnosis (P < 0.001), but a similar rate of symptoms and defibrillators. When compared with the Long-Term phase, patients of the Pilot phase (enrolled in more expert centres) had a more frequent rate of familial disease (P < 0.001), were more frequently diagnosed with a rare underlying disease (P < 0.001), and more frequently implanted with a defibrillator (P = 0.023). Comparing four geographical areas, patients from Southern Europe had a familial disease more frequently (P < 0.001), were more frequently diagnosed in the context of a family screening (P < 0.001), and more frequently diagnosed with a rare underlying disease (P < 0.001). ................................................................................................................................................................................................... Conclusion By providing contemporary observational data on characteristics and management of patients with cardiomyopathies, the registry provides a platform for the evaluation of guideline implementation. Potential gaps with existing recommendations are discussed as well as some suggestions for improvement of health care provision in Europe