BACKGROUND: Pathogenic variants of MYH7, which encodes the beta-myosin heavy chain protein, are major causes of dilated and hypertrophic cardiomyopathy.
METHODS: In this study, we used whole-genome sequencing data to identify MYH7 variants in 397 patients with various cardiomyopathy subtypes who were participating in the National Project of Bio Big Data pilot study in Korea. We also performed in silico analyses to predict the pathogenicity of the novel variants, comparing them to known pathogenic missense variants.
RESULTS: We identified 27 MYH7 variants in 41 unrelated patients with cardiomyopathy, consisting of 20 previously known pathogenic/likely pathogenic variants, 2 variants of uncertain significance, and 5 novel variants. Notably, the pathogenic variants predominantly clustered within the myosin motor domain of MYH7. We confirmed that the novel identified variants could be pathogenic, as indicated by high prediction scores in the in silico analyses, including SIFT, Mutation Assessor, PROVEAN, PolyPhen-2, CADD, REVEL, MetaLR, MetaRNN, and MetaSVM. Furthermore, we assessed their damaging effects on protein dynamics and stability using DynaMut2 and Missense3D tools.
CONCLUSIONS: Overall, our study identified the distribution of MYH7 variants among patients with cardiomyopathy in Korea, offering new insights for improved diagnosis by enriching the data on the pathogenicity of novel variants using in silico tools and evaluating the function and structural stability of the MYH7 protein.

Hypertrophic cardiomyopathy (HCM) is a common cardiovascular condition in cats, affecting yth males and females of all ages. Some breeds, such as Ragdolls and Maine Coons, can develop HCM at a young age. The disease has a wide range of progression and severity, characterized by various pathological changes in the heart, including arteritis, fibrous tissue deposition, and myocardial cell hypertrophy. Left ventricular hypertrophy, which can restrict blood flow, is a common feature of HCM. The disease may persist into old age and eventually lead to heart failure and increased diastolic pressure. The basis of HCM in cats is thought to be genetic, although the exact mechanisms are not fully understood. Mutations in sarcomeric proteins, in particular myosin-binding protein C (MYBPC3), have been identified in cats with HCM. Two specific mutations, MYBPC3 [R818W] and MYBPC3 [A31P], have been classified as \'pathogenic\'. Other variants in genes such as MYBPC3, TNNT2, ALMS1, and MYH7 are also associated with HCM. However, there are cases where cats without known genetic mutations still develop HCM, suggesting the presence of unknown genetic factors contributing to the disease. This work aims to summarise the new knowledge of HCM in cats and the alterations in cardiac tissue as a result of genetic variants.

UNASSIGNED: Lung cancer is one of the major cause of death globally. Crizotinib is a first-line drug used in treating non-small-cell lung cancer (NSCLC). However, the pathophysiological mechanisms underlying its cardiotoxicity are unknown. This study investigated the mechanisms of crizotinib-induced cardiotoxicity and explored whether this toxicity can be prevented by the angiotensin receptor/neprilysin inhibitor sacubitril/valsartan.
UNASSIGNED: Male C57BL/6 mice were randomly divided into three groups: control, crizotinib (40 mg ⋅ kg - 1 ⋅ d - 1 for four weeks), and crizotinib + sacubitril/valsartan (40 mg ⋅ kg - 1 ⋅ d - 1 /60 mg ⋅ kg - 1 ⋅ d - 1 for four weeks). Expression of genes in myocardial tissue were detected by transcriptomic sequencing, with verification of the differentially expressed genes (DEGs) using Real time-polymerase chain reaction (RT-PCR). Blood pressure (BP) and cardiac function of animals were measured using non-invasive monitoring and echocardiography approaches. Ventricular refractory period (RP), as well as the induction rate and score of ventricular arrhythmias (VAs) were detected by in vivo electrophysiology. Epicardial conductance was measured by mapping. Expression of Myh7 in myocardium was detected by western blot and RT-PCR.
UNASSIGNED: DEGs detected using transcriptomic sequencing included 10 up-regulated and 20 down-regulated genes. The first 5 DEGs identified were Myh7, Ngp, Lcn2, Ciart and Ptgds. Kyoto Encyclopedia of Genes and Genomes (KEGG) result indicated that Myh7 is involved in myocarditis, cardiomyopathy, and cardiac muscle contraction. Crizotinib treatment increased blood pressure, prolonged QTc interval, shortened ventricular RP, increased the incidence and score of right VAs, and increased Myh7 expression. Most of these responses were limited by sacubitril/valsartan.
UNASSIGNED: Crizotinib induced a range of cardiotoxic side effects in a mouse model and increased Myh7 expression represents a biomarker for this response. These cardiovascular toxic responses can be largely prevented by sacubitril/valsartan.

Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.

BACKGROUND: Catalogues of pathogenic genetic mutations in hypertrophic cardiomyopathy (HCM) are disproportionately small when compared to that of the size of the population with South Asian ancestry and their collective increased risk of heart disease.
METHODS: We conducted clinical exome sequencing of 200 HCM patients to identified cardiomyopathy-associated genetic mutations. The clinical and echocardiographic characteristics of genotype-positive and genotype-negative patients were compared, and the likelihood of detecting a positive genetic test result was evaluated. Allelic burden analysis was done to compare the minor allele frequencies (MAF) of the pathogenic or likely pathogenic (P/LP) variants and variants of uncertain significance (VUSs) identified in the cohort against various population genomics databases.
RESULTS: The genetic yield was 40% for P/LP variants, with MYBPC3 and MYH7 as the predominant sarcomere genes. Younger age-at-diagnosis, family history of HCM, asymmetric hypertrophic (ASH) pattern, the ratio of the interventricular septum to posterior wall thickness (IVS/PW ratio), left atrial (LA) dimensions, severe mitral regurgitation grade (MR grade), late gadolinium enhancement (LGE) detected fibrosis and absence of hypertension were associated with an increased likelihood of HCM-associated variants. Patients who experienced ventricular tachycardia and premature cardiovascular death were significantly likely to carry MYBPC3 or loss-of-function variants. LA and interventricular septal (IVS) dimensions were associated with MYH7 variants. The rare variant burden for P/LP variants and VUSs was significantly enriched in HCM cases compared to population controls.
CONCLUSIONS: Our study provides a comprehensive evaluation of HCM-associated genetic mutations from an Indian population. The identified genotype-phenotype associations could improve the yield of targeted genetic testing in HCM.

Determining the pathogenicity of hypertrophic cardiomyopathy-associated mutations in the β-myosin heavy chain (MYH7) can be challenging due to its variable penetrance and clinical severity. This study investigates the early pathogenic effects of the incomplete-penetrant MYH7 G256E mutation on myosin function that may trigger pathogenic adaptations and hypertrophy. We hypothesized that the G256E mutation would alter myosin biomechanical function, leading to changes in cellular functions. We developed a collaborative pipeline to characterize myosin function across protein, myofibril, cell, and tissue levels to determine the multiscale effects on structure-function of the contractile apparatus and its implications for gene regulation and metabolic state. The G256E mutation disrupts the transducer region of the S1 head and reduces the fraction of myosin in the folded-back state by 33%, resulting in more myosin heads available for contraction. Myofibrils from gene-edited MYH7WT/G256E human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exhibited greater and faster tension development. This hypercontractile phenotype persisted in single-cell hiPSC-CMs and engineered heart tissues. We demonstrated consistent hypercontractile myosin function as a primary consequence of the MYH7 G256E mutation across scales, highlighting the pathogenicity of this gene variant. Single-cell transcriptomic and metabolic profiling demonstrated upregulated mitochondrial genes and increased mitochondrial respiration, indicating early bioenergetic alterations. This work highlights the benefit of our multiscale platform to systematically evaluate the pathogenicity of gene variants at the protein and contractile organelle level and their early consequences on cellular and tissue function. We believe this platform can help elucidate the genotype-phenotype relationships underlying other genetic cardiovascular diseases.

Pathogenic variants in MYH7 and MYBPC3 account for the majority of hypertrophic cardiomyopathy (HCM). Targeted drugs like myosin ATPase inhibitors have not been evaluated in children. We generate patient and variant-corrected iPSC-cardiomyocytes (CMs) from pediatric HCM patients harboring single variants in MYH7 (V606M; R453C), MYBPC3 (G148R) or digenic variants (MYBPC3 P955fs, TNNI3 A157V). We also generate CMs harboring MYBPC3 mono- and biallelic variants using CRISPR editing of a healthy control. Compared with isogenic and healthy controls, variant-positive CMs show sarcomere disorganization, higher contractility, calcium transients, and ATPase activity. However, only MYH7 and biallelic MYBPC3 variant-positive CMs show stronger myosin-actin binding. Targeted myosin ATPase inhibitors show complete rescue of the phenotype in variant-positive CMs and in cardiac Biowires to mirror isogenic controls. The response is superior to verapamil or metoprolol. Myosin inhibitors can be effective in genotypically diverse HCM highlighting the need for myosin inhibitor drug trials in pediatric HCM.

Background: Hypertrophic cardiomyopathy (HCM) is a genetic condition with a prevalence of 1:500-1:3 000. Variants in genes encoding sarcomeric proteins are mainly responsible for the disease. MYH7 gene encoding a myosin heavy chain beta, together with MYPBC3 gene are the two most commonly affected genes. The clinical presentation of this disease varies widely between individuals. This study aims to report a variant of MYH7 responsible for HCM in a five-generation family with a history of cardiac problems. Methods: The diagnosis was established according to the European Society of Cardiology HCM criteria based on two-dimensional Doppler echocardiography or cardiovascular magnetic resonance. Genetic analysis was performed using next-generation-sequencing and Sanger method. Results: The medical history of the presented family began with a prenatal diagnosis of HCM in the first child of a family with previously healthy parents. Five generations of the family had a long history of sudden cardiac death and cardiac problems. A NM_000257.4:c.2342T>A (p.Leu781Gln) variant was detected in the MYH7 gene. It was heterozygous in the proband and in all affected individuals in a large family. The variant was present in 10 affected members of the family, and was absent in 7 members. The clinical course of the disease was severe in several members of the family: three family members died of sudden cardiac death, one patient required heart transplantation, three underwent septal myectomy, and three required implantable cardioverter defibrillator (ICD) implantation. Conclusion: Herein, we report a MYH7 variant responsible for HCM. Familial HCM is inherited primarily in autosomal dominant mode, which is in accordance with our study. However, the presented family showed a broad clinical spectrum of HCM. Out of 10 family members with positive genetic testing 8 had severe presentation of the disease and 2 had a mild phenotype. This suggests that the severity of the disease may depend on other factors, most likely genetic.

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder characterized by marked clinical and genetic heterogeneity. Ethnic groups underrepresented in studies may have distinctive characteristics. We sought to evaluate the clinical and genetic landscape of Russian HCM patients. A total of 193 patients (52% male; 95% Eastern Slavic origin; median age 56 years) were clinically evaluated, including genetic testing, and prospectively followed to document outcomes. As a result, 48% had obstructive HCM, 25% had HCM in family, 21% were asymptomatic, and 68% had comorbidities. During 2.8 years of follow-up, the all-cause mortality rate was 2.86%/year. A total of 5.7% received an implantable cardioverter-defibrillator (ICD), and 21% had septal reduction therapy. A sequencing analysis of 176 probands identified 64 causative variants in 66 patients (38%); recurrent variants were MYBPC3 p.Q1233* (8), MYBPC3 p.R346H (2), MYH7 p.A729P (2), TPM1 p.Q210R (3), and FLNC p.H1834Y (2); 10 were multiple variant carriers (5.7%); 5 had non-sarcomeric HCM, ALPK3, TRIM63, and FLNC. Thin filament variant carriers had a worse prognosis for heart failure (HR = 7.9, p = 0.007). In conclusion, in the Russian HCM population, the low use of ICD and relatively high mortality should be noted by clinicians; some distinct recurrent variants are suspected to have a founder effect; and family studies on some rare variants enriched worldwide knowledge in HCM.

The MYH7 gene, which encodes the slow/ß-cardiac myosin heavy chain, is mutated in myosin storage myopathy (MSM). The clinical spectrum of MSM is quite heterogeneous in that it ranges from cardiomyopathies to skeletal myopathies or a combination of both, depending on the affected region. In this study, we performed clinical and molecular examinations of the proband of an Iranian family with MSM in an autosomal dominant condition exhibiting proximal muscle weakness and dilated cardiomyopathy.
Following thorough clinical and paraclinical examinations, whole-exome sequencing `was performed on the proband (II-5). Pathogenicity prediction of the candidate variant was performed through in-silico analysis. Co-segregation analysis of the WES data among the family members was carried out by PCR-based Sanger sequencing.
A novel heterozygous missense variant, MYH7 (NM_000257): c.C1888A: p.Pro630Thr, was found in the DNA of the proband and his children and confirmed by Sanger sequencing. The in-silico analysis revealed that p.Pro630Thr substitution was deleterious. The novel sequence variant fell within a highly conserved region of the head domain. Our findings expand the spectrum of MYH7 mutations.
This finding could improve genetic counseling and prenatal diagnosis in families with clinical manifestations associated with MYH7-related myopathy.