Aim To study the clinical course of the mixed phenotype (hypertrophic cardiomyopathy, HCMP, and left ventricular noncompaction, LVNC); to determine its genetic causes; and to evaluate incidence of car Show more
Aim To study the clinical course of the mixed phenotype (hypertrophic cardiomyopathy, HCMP, and left ventricular noncompaction, LVNC); to determine its genetic causes; and to evaluate incidence of cardiovascular complications (CVC) during the follow-up period.Material and methods In screening of 286 patients with HCMP, 8 of them (2.8 %; median age, 41.5 years; 4 men and 4 women) from unrelated families were found to have the mixed phenotype (combination of HCMP and LVNC). For their 10 first-degree relatives, the most frequent phenotype was HCMP without LVNC; however, both isolated LVNC and the mixed phenotype were also observed. Criteria for HCMP and LVNC were confirmed by echocardiography and cardiac magnetic resonance imaging Genotyping was performed by high-throughput sequencing NGT using the TruSight Cardio Sequencing Panel kit.Results Probands with the HCMP+LVNC combination compared to first-degree relatives with isolated HCMP and LVNC were characterized by more pronounced left ventricular dysfunction (ejection fraction, 43.57±7.6 and 53.64±6.51 %, respectively; p<0.001), a higher risk of CVC, and a higher incidence of ventricular tachyarrhythmias (7.9 and 2.2 %, respectively; p<0.01). 11 mutations in 5 genes were found in 8 patients with the mixed phenotype. 72.7 % of mutations were in the MYH7 and MYBPC3 genes that encode the heavy chain of β-myosin and myosin-binding protein C, respectively; however, in some cases, replacements in other genes (DTNA, TGFB2) were also found.Conclusion The mixed phenotype (HCMP and LVNC) is associated with more severe clinical course of the disease and unfavorable CVC. Show less
Hypertrophic cardiomyopathy is a common genetic cardiac disease. Prevention and early diagnosis of this disease are very important. Because of the large number of causative genes and the high rate of Show more
Hypertrophic cardiomyopathy is a common genetic cardiac disease. Prevention and early diagnosis of this disease are very important. Because of the large number of causative genes and the high rate of mutations involved in the pathogenesis of this disease, traditional methods of early diagnosis are ineffective. We developed a custom AmpliSeq panel for NGS sequencing of the coding sequences of ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, TPM1, and CASQ2. A genetic analysis of student cohorts (with and without cardiomyopathy risk in their medical histories) and patients with cardiomyopathies was performed. For the statistical and bioinformatics analysis, Polyphen2, SIFT, SnpSift and PLINK software were used. To select genetic markers in the patients with cardiomyopathy and in the students of the high risk group, four additive models were applied. Our AmpliSeq custom panel allowed us to efficiently explore targeted sequences. Based on the score analysis, we detected three substitutions in the MYBPC3 and CASQ2 genes and six combinations between loci in the MYBPC3, MYH7 and CASQ2 genes that were responsible for cardiomyopathy risk in our cohorts. We also detected substitutions in the TNNT2 gene that can be considered as protective against cardiomyopathy. We used NGS with AmpliSeq libraries and Ion PGM sequencing to develop improved predictive information for patients at risk of cardiomyopathy. Show less