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Key Clinical Message.: A 15‐year‐old girl developed inherited cardiomyopathy and macrothrombocytopenia revealing pathogenic variants of both MYH7 and MYH9 genes. This underlies the importance of repeated genetic testing in diagnosing and managing inherited disorders. The MYH7 and MYH9 genes encode for distinct myosin heavy chain proteins. Our case features a 15‐year‐old girl, presenting with inherited cardiomyopathy and macrothrombocytopenia, revealing distinct pathogenic variants of both MYH7 and MYH9 genes. This underlines the relevance of genetic testing and personalized medicine in diagnosing and managing inherited disorders. [ABSTRACT FROM AUTHOR]

MYH7, encoding the myosin heavy chain sarcomeric β‐myosin heavy chain, is a common cause of both hypertrophic and dilated cardiomyopathy. Additionally, families with left ventricular noncompaction cardiomyopathy (LVNC) and congenital heart disease (CHD), typically septal defects or Ebstein anomaly, have been identified to have heterozygous pathogenic variants in MHY7. One previous case of single ventricle CHD with heart failure due to a MYH7 variant has been identified. Herein, we present a single center's experience of complex CHD due to MYH7 variants. Three probands with a history of CHD, LVNC, and/or arrhythmias were identified to have MYH7 variants through multigene panel testing or exome sequencing. These three patients collectively had 12 affected family members, four with a history of Ebstein anomaly and seven with a history of LVNC. These findings suggest a wider phenotypic spectrum in MYH7‐related CHD than previously understood. Further investigation into the possible role of MYH7 in CHD and mechanism of disease is necessary to fully delineate the phenotypic spectrum of MYH7‐related cardiac disease. MYH7 should be considered for families with multiple individuals with complex CHD in the setting of a family history of LVNC or arrhythmias. [ABSTRACT FROM AUTHOR]

Background: Although genetic variants in MYH7 are the most frequent cause of pediatric genetic dilated cardiomyopathy (DCM), there are no studies available describing this entity. We sought to describe clinical features, analyze variant location, and explore predictors of bad prognosis in pediatric MYH7 -related DCM., Methods and Results: We evaluated clinical records from 44 patients (24 men; median age at diagnosis, 0.54 [interquartile range, 0.01-10.8] years) with pathogenic/likely pathogenic variants in MYH7 diagnosed with DCM at pediatric age (<18 years) followed at 13 international centers. We also explored risk factors associated with a composite end point of end-stage heart failure defined as heart transplantation or heart failure-related death. Twenty-two patients (50%) were diagnosed at age <6 months, including 7 (16%) at birth. Left ventricular (LV) hypertrabeculation features were present in 15 (38%), particularly among patients with genetic variants in the head domain. After a median follow-up of 6.1 years (interquartile range, 1.9-13.4), 15 patients (36%) required a heart transplant (n=14) or died due to end-stage heart failure (n=1), 15 patients (36%) persisted with systolic dysfunction despite treatment, 12 (29%) had a significant increase in LV ejection fraction, and 2 were lost to follow-up. Overall, end-stage heart failure event rate was 25% at 5 years. New York Heart Association class III to IV (hazard ratio [HR], 7.67 [95% CI, 2.16-27.2]; P =0.002) and LV ejection fraction ≤35% (HR, 4.00 [95% CI, 1.11-14.4]; P =0.03) were the best predictors of bad prognosis., Conclusions: Pediatric MYH7 -related DCM is characterized by early onset, frequent LV hypertrabeculation, and poor prognosis. Advanced New York Heart Association class and low LV ejection fraction emerged as predictors of end-stage heart failure.

Background: Laing myopathy is characterized by broad clinical and pathological variability. They are limited in number and protocol of study. We aimed to delineate muscle imaging profiles and validate imaging analysis as an outcome measure. Methods: This was a cross‐sectional and longitudinal cohort study. Data from clinical, functional and semi‐quantitative muscle imaging (60 magnetic resonance imaging [MRI] and six computed tomography scans) were studied. Hierarchical analysis, graphic heatmap representation and correlation between imaging and clinical data using Bayesian statistics were carried out. Results: The study cohort comprised 42 patients from 13 families harbouring five MYH7 mutations. The cohort had a wide range of ages, age at onset, disease duration, and myopathy extension and Gardner‐Medwin and Walton (GMW) functional scores. Intramuscular fat was evident in all but two asymptomatic/pauci‐symptomatic patients. Anterior leg compartment muscles were the only affected muscles in 12% of the patients. Widespread extension to the thigh, hip, paravertebral and calf muscles and, less frequently, the scapulohumeral muscles was commonly observed, depicting distinct patterns and rates of progression. Foot muscles were involved in 40% of patients, evolving in parallel to other regions with absence of a disto‐proximal gradient. Whole cumulative imaging score, ranging from 0 to 2.9 out of 4, was associated with disease duration and with myopathy extension and GMW scales. Follow‐up MRI studies in 24 patients showed significant score progression at a variable rate. Conclusions: We confirmed that the anterior leg compartment is systematically affected in Laing myopathy and may represent the only manifestation of this disorder. However, widespread muscle involvement in preferential but variable and not distance‐dependent patterns was frequently observed. Imaging score analysis is useful to categorize patients and to follow disease progression over time. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to identify the genetic causes of patients with hypertrophic cardiomyopathy (HCM) within a family. Most of the previous studies found point mutations as the genetic causes for HCM, whole‐gene deletion was rarely reported. Methods: Although, clinical genetic testing has been widely used for identifying variants in HCM patients, structural variations are understudied, partly owing to the inadequacy of the available methodology. In the present study, whole‐exome sequencing (WES) and Sanger sequencing validation was used to identify the genetic causes in patients with familial HCM. Results: A genomic deletion in Chromosome 19 containing the whole of troponin I3 gene (TNNI3), and the p.Ile736Thr variant in the myosin heavy chain 7 gene (MYH7) were identified in two patients with familial HCM by WES. The p.Ile736Thr variant is further validated by Sanger sequencing and is predicted as a pathogenic variant by in silico analysis. Conclusion: We added the notion that not only p.Ile736Thr variant of MYH7, but also TNNI3 deletion might potentially contribute to HCM pathogenesis. Our study also suggested WES was a powerful tool to identify the genetic variants causing HCM. [ABSTRACT FROM AUTHOR]

MYH7‐related disease (MRD) is the most common hereditary primary cardiomyopathy (CM), with pathogenic MYH7 variants accounting for approximately 40% of familial hypertrophic CMs. MRDs may also present as skeletal myopathies, with or without CM. Since pathogenic MYH7 variants result in highly variable clinical phenotypes, from mild to fatal forms of cardiac and skeletal myopathies, genotype–phenotype correlations are not always apparent, and translation of the genetic findings to clinical practice can be complicated. Data on genotype–phenotype correlations can help facilitate more specific and personalized decisions on treatment strategies, surveillance, and genetic counseling. We present a series of six MRD pedigrees with rare genotypes, encompassing various clinical presentations and inheritance patterns. This study provides new insights into the spectrum of MRD that is directly translatable to clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: MYH7 gene mutations are related to a heterogeneous group of skeletal and cardiac myopathies.Methods: We evaluated clinical and muscle MRI changes in patients with mutations in the rod domain of MYH7, including 1 with mosaicism and 3 with novel missense mutations.Results: Patients presented in childhood with a distal and axial phenotype. Biopsy findings were variable. Half of the cases displaying some type of core pathology, including minicores and eccentric cores. Most patients demonstrated internal bands of infiltration ("inverted-collagen-VI sign") in multiple muscles, particularly the soleus, and prominent atrophy and fatty infiltration of the tongue and the paraspinal, gluteus minimus, sartorius, gracilis, tibialis anterior, and extensor digitorum longus muscles.Discussion: Muscle imaging findings in patients with axial involvement provide significant clues permitting the distinction between MYH7-related myopathies and other axial myopathies such as those related to SEPN1 and LMNA genes. Muscle Nerve 58: 224-234, 2018. [ABSTRACT FROM AUTHOR]

Key Clinical Message We think that the main interests of this study are the report of a new mutation in gene MYBPC3 as a cause of Hypertrophic cardiomyopathy (HMC), and the verification of the fact that not always is the number of mutations related to the severity of the disease. [ABSTRACT FROM AUTHOR]

To search for genes associated with migratory phenotypes in songbirds, we selected candidate genes through annotations from the Mouse Genome Informatics database and assembled an extensive candidate-gene library. Then, we implemented a next-generation sequencing approach to obtain DNA sequences from the Painted Bunting genome. We focused on those sequences that were conserved across avian species and that aligned with candidate genes in our mouse library. We genotyped short sequence repeats from the following candidate genes: ADRA1d, ANKRD17, CISH and MYH7. We studied the possible correlations between allelic variations occurring in these novel candidate migration genes and avian migratory phenotypes available from the published literature. We found that allele variation at MYH7 correlated with a calculated index of speed of migration (km/day) across 11 species of songbirds. We highlight the potential of the Mouse Genome Informatics database in providing new candidate genes that might play a crucial role in regulating migration in birds and possibly in other taxa. Our research effort shows the benefits and limitations of working with extensive genomic datasets and offers a snapshot of the challenges related to cross-species validation in behavioral and molecular ecology studies. [ABSTRACT FROM AUTHOR]

The chicken is a well-established model for amniote (including human) skeletal muscle formation because the developmental anatomy of chicken skeletal muscle matches that of mammals. The accessibility of the chicken in the egg as well as the sequencing of its genome and novel molecular techniques have raised the profile of this model. Over the years, a number of regulatory and marker genes have been identified that are suited to monitor the progress of skeletal myogenesis both in wildtype and in experimental embryos. However, in the various studies, differing markers at different stages of development have been used. Moreover, contradictory results on the hierarchy of regulatory factors are now emerging, and clearly, factors need to be able to cooperate. Thus, a reference paper describing in detail and side-by-side the time course of marker gene expression during avian myogenesis is needed. We comparatively analysed onset and expression patterns of the key markers for the chicken immature paraxial mesoderm, for muscle-competent cells, for cells committed to myogenesis and for cells entering terminal differentiation. We performed this analysis from stages when the first paraxial mesoderm is being laid down to the stage when mesoderm formation comes to a conclusion. Our data show that, although the sequence of marker gene expression is the same at the various stages of development, the timing of the expression onset is quite different. Moreover, marker gene expression in myogenic cells being deployed from the dorsomedial and ventrolateral lips of the dermomyotome is different from those being deployed from the rostrocaudal lips, suggesting different molecular programs. Furthermore, expression of Myosin Heavy Chain genes is overlapping but different along the length of a myotube. Finally, Mef2c is the most likely partner of Mrf proteins, and, in contrast to the mouse and more alike frog and zebrafish fish, chicken Mrf4 is co-expressed with MyoG as cells enter terminal differentiation. [ABSTRACT FROM AUTHOR]

The function of the stress-responsive N-myc downstream-regulated gene 2 (NDRG2) in the control of myoblast growth, and the amino acids contributing to its function, are not well characterized. Here, we investigated the effect of increased NDRG2 levels on the proliferation, differentiation and apoptosis in skeletal muscle cells under basal and stress conditions. NDRG2 overexpression increased C2C12 myoblast proliferation and the expression of positive cell cycle regulators, cdk2, cyclin B and cyclin D, and phosphorylation of Rb, while the serine/threonine-deficient NDRG2, 3A-NDRG2, had less effect. The onset of differentiation was enhanced by NDRG2 as determined through the myogenic regulatory factor expression profiles and myocyte fusion index. However, the overall level of differentiation in myotubes was not different. While NDRG2 up-regulated caspase 3/7 activities during differentiation, no increase in apoptosis was measured by TUNEL assay or through cleavage of caspase 3 and PARP proteins. During H 2 O 2 treatment to induce oxidative stress, NDRG2 helped protect against the loss of proliferation and ER stress as measured by GRP78 expression with 3A-NDRG2 displaying less protection. NDRG2 also attenuated apoptosis by reducing cleavage of PARP and caspase 3 and expression of pro-apoptotic Bax while enhancing the pro-survival Bcl-2 and Bcl-xL levels. In contrast, Mcl-1 was not altered, and NDRG2 did not protect against palmitate-induced lipotoxicity. Our findings show that NDRG2 overexpression increases myoblast proliferation and caspase 3/7 activities without increasing overall differentiation. Furthermore, NDRG2 attenuates H 2 O 2 -induced oxidative stress and specific serine and threonine amino acid residues appear to contribute to its function in muscle cells. [ABSTRACT FROM AUTHOR]

We report on two prenatal ultrasound diagnoses of left ventricular non-compaction cardiomyopathy (LVNC) associated taith mutation of the cardiac β-myosin heavy chain gene fMYHyj. LVNC is characterized by a trabecular meshwork and deep intertrabecular myocardial recesses communicating with the left ventricular cavity. Clinical features range from non-penetrant disease in adult carriers to heart failure, arrhythmia and thromboembolism. Both cases showed cardiomegaly on prenatal ultrasound examinations, with features indicating non-compaction of the myocardium apparent in the third trimester. Mutations in the MYH7 gene were identified postnatally in each case in both the proband and the father. One infant underwent surgical mitral valvuloplasty and a mechanical valve implant later; in the other, left ventricular function was unimpaired at birth. Cardiac function in both cases remained stable at last follow-up. These cases highlight the importance of prenatal ultrasound diagnosis of LVNC and the need for cardiologic and molecular testing of first-degree relatives who may be unknown carriers of an MYH7 mutation [ABSTRACT FROM AUTHOR]

Background: Congenital myopathies (CM) were traditionally classified according to the muscle histopathological features, but in recent years, molecular diagnosis has become increasingly important. CM may present a wide phenotype variability, and while adult-onset CM have been increasingly recognized, substantial diagnostic delays are still reported., Objectives: To describe a cohort of adult CM patients, including clinical, genetic, and histopathological features, and further characterize the subgroup of adult-diagnosed patients., Materials and Methods: We performed a retrospective observational cohort study to characterize the CM patients evaluated in our adult Neuromuscular outpatient clinic, including the subgroup of adult-diagnosed patients., Results: We identified 19 CM patients with compatible molecular and/or histological diagnoses, of which 14 were diagnosed in adulthood. Eleven adult-diagnosed patients had symptoms since childhood and 9 had a family history of myopathy. The median age of symptoms' onset was 4 years old and the median age at diagnosis was 37 years old. The most common causative gene was RYR1, followed by TTN and MYH7. Three patients had non-specific features on muscle biopsy, all diagnosed during adulthood., Conclusions: In our cohort, the majority of CM were diagnosed in adulthood, despite most having pediatric-onset symptoms and positive family history. The diagnostic delay may be associated with mild presentation, slow course, atypical muscle histology, and lack of awareness of adult-onset CM. Studies with larger populations are needed., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Muelas N, Hackman P, Luque H, Suominen T, Espinós C, Garcés-Sánchez M, Sevilla T, Azorín I, Millán JM, Udd B, Vílchez JJ. Spanish MYH7 founder mutation of Italian ancestry causing a large cluster of Laing myopathy patients. Laing myopathy is a distal myopathy caused by mutations in the tail of the slow beta-myosin heavy chain gene MYH7. A large cluster of patients belonging to different families, with Laing myopathy due to p.K1729del mutation, was found in the Safor region, Spain. The same mutation was previously reported in an American family with Italian ancestry. The possibility that p.K1729del in MYH7 might be a founder mutation in the Safor patients and the chance of a common origin with the Italian-American family mutation was investigated by haplotype analyses, mutation data origin estimation and historical inquiry. Our results show that the p.K1729del in MYH7 harboured by patients from the Safor indeed is a founder mutation. A common ancestral origin of this mutation in the Spanish and Italian families is also suggested because they all share a core SNP haplotype at locus MYH7. Data estimation yields the origin of the mutation in the Safor at the beginning of the XVII century, when the Moorish were spelt and the region was resettled with Italian families. [ABSTRACT FROM AUTHOR]

Left ventricular noncompaction (LVNC) is a relatively common genetic cardiomyopathy, characterized by prominent trabeculations with deep intertrabecular recesses in mainly the left ventricle. Although LVNC often occurs in an isolated entity, it may also be present in various types of congenital heart disease (CHD). The most prevalent CHD in LVNC is Ebstein anomaly, which is a rare form of CHD characterized by apical displacement and partial fusion of the septal and posterior leaflet of the tricuspid valve with the ventricular septum. Several reports of sporadic as well as familial cases of Ebstein anomaly associated with LVNC have been reported. Recent studies identified mutations in the MYH7 gene, encoding the sarcomeric β-myosin heavy chain protein, in patients harboring this specific phenotype. Here, we will review the association between Ebstein anomaly, LVNC and mutations in MYH7, which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance., (Copyright © 2013 Wiley Periodicals, Inc.)