The combination of left ventricular non-compaction and hypertrophic cardiomyopathy in one family with a pathogenic variant in the MYBPC3 gene (rs397516037)

The article presents the results of clinical, instrumental and molecular genetic tests of three generations of a family with inherited cardiomyopathy caused by a new variant in the MYBPC3 gene. A specific feature of this case is the phenotypic heterogeneity of the mutation — a combination of hypertrophic cardiomyopathy and left ventricular non-compaction in family members. Attention is drawn to the various severity of clinical manifestations in relatives of carriers of mutation: from asymptomatic to severe heart failure and acute cerebrovascular accident.

Combined PTPN11 and MYBPC3 Gene Mutations in an Adult Patient with Noonan Syndrome and Hypertrophic Cardiomyopathy

In this report, an atypical case of Noonan syndrome (NS) associated with sarcomeric hypertrophic cardiomyopathy (HCM) in a 33-year-old patient was described. Genetic testing revealed two different disease-causing mutations: a mutation in the PTPN11 gene, explaining NS, and a mutation in the MYBPC3 gene, known to be associated with HCM. This case exemplifies the challenge in achieving a definite etiological diagnosis in patients with HCM and the need to exclude other diseases mimicking this condition (genocopies or phenocopies). Compound heterozygous mutations are rare but possible in HCM patients. In conclusion, this study highlights the important role of genetic testing as a necessary diagnostic tool for performing a definitive etiological diagnosis of HCM.

P890Gene carriers of hypertrophic cardiomyopathy, what to expect over time

Background Data on the natural history of genotype positive/phenotype negative (G+/P-) hypertrophic cardiomyopathy (HCM) patients identified as a part of genetic cascade screening in different age groups is limited. Purpose To describe the rate of conversion to overt HCM phenotype in G+/P- subjects in relation with the age who were identified in a specialized clinic in a single center. Methods We retrospectively identified 56 consecutive HCM G+/P− subjects followed in our center specialized clinic between Jan 2012-Jan 2019. Demographics, family history of sudden cardiac death (SCD) and presence of symptoms were collected. All of them underwent baseline investigations including ECG, echocardiogram and/or cardiac magnetic resonance (CMR) and 24 hour monitor at baseline and during follow up. Overt HCM phenotype was defined as left ventricular hypertrophy (LVH) ≥13mm in the echocardiogram or CMR. Results We identified 56 HCM G+/P− subjects from 34 different families. 22 subjects were ≤18 years old with a mean age of 11.6±0.9 years (IQR [P25-P75] 9–16 years) and 32 subjects were >18 years old with a mean age of 38.1±2.2 years (IQR [P25-P75] 27–48 years). Mean time of follow up was 35.2±34.4 months (IQR [P25-P75] 4.25–50.25 years). 60.7% (34) of them were female and 82.1% (46) were of Caucasian ethnicity. Most of the subjects with no evidence LVH were asymptomatic but small number had symptoms, 8.9% (5), and 3.6% (2) were treated with betablockers for palpitations. Family history of SCD was present in 57.1% (32) of the subjects and 35.7% (20) had a relative with an implantable cardiac defibrillator (ICD). MYBPC3 gene mutations were identified in 62.5% (35) of subjects, followed by MYH7 gene mutation in 23.2% (13) of the cases. None of the subjects under 18 year old developed HCM during the period of observation, however 7 subjects (21.9%), mean age 48.6±10.5 years, 71.4% (5) females, showed progression to HCM in the >18 years old group. All of them had pathogenic MYBPC3 gene variants. No differences were found in gender, ethnicity, symptoms or family history of SCD in the G+/P− vs HCM group. There were no differences on the presence of ECG abnormalities and no episodes of NSVT were recorded in any of the groups. Baseline E/e' values of those with new HCM vs G+/P− were higher (8.2±3.3 vs 5.6±1.7, p=0.014). Conclusions In our cohort, rate of progression to HCM phenotype was 21.9% of >18 years old HCM G+/P- subjects. The mean age at the time of developing the phenotype was 48.6±10.5 years old and all the patients were asymptomatic for cardiac symptoms. Echocardiographic E/e' values were increased. This data supports the need of life long follow up of this group of patients with ongoing clinical evaluation. Acknowledgement/Funding ESC clinical grant

Mutation spectrum in sarcomeric protein genes and their phenotypic features in Belarusian patients with hypertrophic cardiomyopathy

Введение. Гипертрофическая кардиомиопатия (ГКМП) относится к наследственной патологии, основной причиной которой являются мутации в генах, кодирующих белковые компоненты миофибрильного аппарата кардиомиоцитов, при этом спектр этих генетических изменений имеет популяционные особенности. Целью данного исследования являлось определение спектра мутаций в генах, кодирующих саркомерные белки, у пациентов с ГКМП из Беларуси, а также изучение взаимосвязей между генотипом и фенотипическими проявлениями заболевания. Материалы и методы. В исследование были включены 340 неродственных пациентов с ГКМП, проживающих в Беларуси. Обнаружение мутаций в кодирующих последовательностях генов ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, TNNС1 и TPM1 у 89 пациентов проводили методом высокопроизводительного секвенирования (NGS). Направленный поиск выявленных методом NGS генетических дефектов осуществлялся методом автоматического секвенирования по Сэнгеру, а также с использованием ПЦР-ПДРФ анализа. Результаты. У 51,7% пациентов методом NGS обнаружены мутации в генах: MYBPC3 (20,2%), MYH7 (16,9%), TPM1 (3,4%), ACTC1 (2,3%), MYL2 (1,1%) и TNNC1 (1,1%). У 6,7% индивидуумов встречались две (5,6%) или три (1,1%) замены. Обнаружены новые мутации p.Ala49Asn, p.Val1407Phe в гене MYH7; р.Tyr501Ser, р.Trp1007fs, р.Tyr1043*, р.Pro1066Arg, p.Arg1138fs, р.Pro1181Gln, р.Cys1202Arg в гене MYBPC3. Установлены часто встречающиеся мутации: р.Gln1233*, р.Ser871Alafs, комбинация р.Glu1265Val+р.Cys1266Arg, р.Gln401* и р.Trp1214Arg в гене MYBPC3, p.Arg403Trp, p.Arg663Cys, p.Arg663His, p.Ala729Pro, p.Glu924Lys и p.Glu1356Lys в гене MYH7. По данным ЭхоКГ-исследования носители мутаций в генах белков саркомера, особенно обладатели миссенс-мутаций в гене MYBPC3, имели более выраженную гипертрофию миокарда и раннюю манифестацию заболевания по сравнению с пациентами без мутаций в этих генах. Для носителей наиболее распространенной среди белорусских пациентов мутации р.Gln1233* характерны позднее начало заболевания, умеренная гипертрофия миокарда левого желудочка, частое развитие фибрилляции предсердий. Выводы. Распределение встречаемости мутаций в генах, кодирующих саркомерные белки, у пациентов с ГКМП из Беларуси не отличалось от других европейских популяций. 84,9% обнаруженных мутаций локализовано в генах MYBPC3 и MYH7. Background. Hypertrophic cardiomyopathy (HCM) is a hereditary pathology, the main cause of which is mutations in the genes encoding the protein components of the myofibril apparatus of cardiomyocytes, and the spectrum of these genetic changes has population features. The aim of the study was to determine the spectrum of mutations in the genes encoding sarcomeric proteins in patients with HCM from Belarus, as well as to study the association between the genotype and the phenotypic manifestations of the disease. Materials and methods. The study included 340 unrelated patients with HCM from Belarus. Mutation detection in the coding sequences of ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, TNNС1 и TPM1 genes was performed by next generation sequencing (NGS) in 89 patients. The directed search for genetic defects detected by the NGS method was carried out by the automatic sequencing method using Sanger and PCR-RFLP analysis. Results. The NGS method allowed to detect mutations in the genes of 51,7% of patients: MYBPC3 (20,2%), MYH7 (16,9%), TPM1 (3,4%), ACTC1 (2,3%), MYL2 (1,1 %) and TNNC1 (1,1%). In 6,7% of individuals two (5,6%) or three (1,1%) substitutions were observed. New mutations were found: p.Ala49Asn, p.Val1407Phe in the MYH7 gene; p.Tyr501Ser, p.Trp1007fs, p.Tyr1043*, p.Pro1066Arg, p.Arg1138fs, p.Pro1181Gln, р.Cys1202Arg in the MYBPC3 gene. The most frequently occurring mutations were identified: p.Gln1233*, p.Ser871Alafs, the combination of the р.Glu1265Val + p.Cys1266Arg, R.Gln401*, and Trp1214Arg in the MYBPC3 gene, p.Glu924Lys and p.Glu1356Lys in the MYH7 gene. According to the ECG study, carriers of mutations in sarcomere protein genes, especially with missense mutations in the MYBPC3 gene, had more severe myocardial hypertrophy and early disease manifestation then patients without mutations in those genes. The p.Gln1233* mutation was the most common among Belarusian patients and characterized by late onset of the disease, mild left ventricular myocardial hypertrophy and the more frequent development of atrial fibrillation. Conclusions. In general, the distribution of mutations in the genes encoding sarcomeric proteins in patients with HCM from Belarus didn’t differ from other European populations. 84,9% of the detected mutations were localized in MYBPC3 and MYH7 genes.