abchf abchf ABC Heart Fail Cardiomyop ABC Heart Fail Cardiomyop 2764-3107 Sociedade Brasileira de Cardiologia - SBC 10.36660/abchf.20240054i Review Article Exploring MYH7 in Cardiomyopathies: Genetic Drivers and Clinical Outcomes 0000-0001-8649-976X Pires Lucas Vieira Lacerda Conception and design of the research Writing of the manuscript and Critical revision of the manuscript for content 1 * 0009-0003-7829-4408 Correia Vinícius Machado Conception and design of the research Writing of the manuscript and Critical revision of the manuscript for content 1 2 * 0000-0003-0982-0307 Lipari Layara Fernanda Vicente Pereira Conception and design of the research Writing of the manuscript and Critical revision of the manuscript for content 1 0000-0002-2612-8040 Andrade Fernanda Almeida Conception and design of the research Writing of the manuscript and Critical revision of the manuscript for content 3 0000-0002-9323-8805 Fernandes Fábio Conception and design of the research Writing of the manuscript and Critical revision of the manuscript for content 1 0000-0002-1116-6554 Madrini Vagner Junior Conception and design of the research Writing of the manuscript and Critical revision of the manuscript for content 1 4 Carvalho Mariana Lombardi Peres de Conception and design of the research Writing of the manuscript and Critical revision of the manuscript for content 1 Napolitano Giovanna Conception and design of the research Writing of the manuscript and Critical revision of the manuscript for content 1 Silva Elisangela Aparecida da Conception and design of the research Writing of the manuscript and Critical revision of the manuscript for content 1 0000-0003-4407-2906 Vilalva Kelvin Henrique Conception and design of the research Writing of the manuscript and Critical revision of the manuscript for content 1 Val Vitória Pelegrino do Conception and design of the research Writing of the manuscript and Critical revision of the manuscript for content 1 0000-0001-5464-1792 Krieger José Eduardo Conception and design of the research; Writing of the manuscript and Critical revision of the manuscript for content 1 Hospital das Clínicas Faculdade de Medicina Universidade de São Paulo São Paulo SP Brazil Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP – Brazil Sírio-Libanês Ensino e Pesquisa São Paulo SP Brazil Sírio-Libanês Ensino e Pesquisa, São Paulo, SP – Brazil Universidade Federal de São Paulo São Paulo SP Brazil Universidade Federal de São Paulo (UNIFESP), São Paulo, SP – Brazil Hospital Israelita Albert Einstein São Paulo SP Brazil Hospital Israelita Albert Einstein, São Paulo, SP – Brazil Vinícius Machado Correia • Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo – Av. Dr. Enéas Carvalho de Aguiar, 44. Postal Code 05403-000, Cerqueira César, São Paulo, SP – Brazil E-mail: viniciusmachado7@gmail.com

No potential conflict of interest relevant to this article was reported.

Lidia Moura

The authors contributed equally to this work

 30 04 2025 04 2025 5 1 e20240054 03 09 2024 12 11 2024 22 01 2025 This is an open-access article distributed under the terms of the Creative Commons Attribution License. Abstract

The MYH7 gene, which encodes the beta-myosin heavy chain, is a critical component in the structural and functional integrity of cardiac and skeletal muscle cells. Variants in MYH7 are among the most common genetic causes of cardiomyopathies, particularly hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), and have also been implicated in restrictive cardiomyopathy (RCM) and left ventricular hypertrabeculation (LVHT). This review explores the molecular mechanisms by which MYH7 variants lead to these diverse phenotypes, focusing on the genotype-phenotype correlations that underlie the clinical manifestations of each condition. MYH7 variants are primarily missense variants concentrated in the myosin head domain, affecting the contractile function of the protein. These variants lead to a wide spectrum of cardiac abnormalities, from thickening of the myocardial walls to dilation of the cardiac chambers. The review also addresses the broader implications of MYH7 mutations, including their role in skeletal myopathies and potential associations with cancer. Understanding the pathogenic mechanisms of MYH7 variants not only increases diagnostic accuracy but also informs the development of targeted therapies. As the integration of genetic knowledge into clinical practice continues to evolve, the MYH7 gene remains a critical focus for advancing the management and treatment of cardiomyopathies, offering patients hope for improved clinical outcomes through precision medicine.

 MYH7 Hypertrophic cardiomyopathy Dilated Cardiomyopathy Genetic Cardiomyopathies Sarcomeric Genes

Exploring MYH7 in Cardiomyopathies: Genetic Drivers and Clinical Outcomes

MYH7 cardiomyopathy spectrum. DCM: dilated cardiomyopathy; HCM: hypertrophic cardiomyopathy; LVHT: left ventricular hypertrabeculation; MACE: major cardiovascular events; RCM: restrictive cardiomyopathy.

Integrating genetics and cardiology: the role of MYH7 in cardiomyopathies

In recent years, the advent of next-generation sequencing (NGS) has revolutionized genetic testing, leading to a closer integration of genetics and cardiology in medical practice. As our understanding of the human genome and its relationship to cardiovascular health deepens, numerous genotype-phenotype associations are being identified, providing essential insights for the diagnosis and treatment of genetic heart disease (GHD). Among the several genes implicated in GHD, MYH7 stands out as one of the most frequently associated, especially in large cohorts involving cardiomyopathies. 1-3 Along with the genes MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3 and ACTC1, the MYH7 gene is part of the group of sarcomeric genes, which are predominantly associated with hypertrophic cardiomyopathy (HCM). In this group, MYH7 and MYBPC3 are the main genes involved.4 Furthermore, MYH7 contributes significantly to dilated cardiomyopathy (DCM) and has also been identified in restrictive cardiomyopathy (RCM) and left ventricular hypertrabeculation (LVHT).5-7 This review explores the convergence of clinical and molecular approaches in the treatment of MYH7-related disorders. By examining the molecular mechanisms underlying these conditions, we aim to advance our understanding of the disease spectrum and its application to clinical practice.

 Gene structure and function MYH7 Gene: structure, domains, and functional significance in muscle contraction

The MYH7 gene (OMIM:160760) encodes the beta-myosin heavy chain, a protein predominantly expressed in cardiac and skeletal muscle cells. Located on chromosome 14q12, the gene spans 22,883 base pairs and comprises 41 exons, with the first two being noncoding and exons 37 and 38, forming a unique fused structure. The full-length protein consists of 1,935 amino acids.8,9 Myosin is an actin-based motor protein with ATPase activity essential for muscle contraction in both cardiac and skeletal muscles. Together with actin thin filaments, myosin constitutes the fundamental contractile unit in muscles (Figure 1).10

– Sarcomere structure, relaxed (a) and contracted (b), highlighting the relation between thin filament (actin) and thick filament (Myosin), compounding the major contractile structure of muscle cells.

MYH7 is structurally divided into three major domains: the Myosin N-terminal SH3-like domain (amino acids 31-81); the myosin-head domain, which contains the motor unit (amino acids 85-778) and the IQ domain (amino acids 781-810); and the myosin-tail domain (amino acids 839-1935), which consists of repeating 28-amino-acid patterns forming an alpha-helical coiled-coil structure.10,11 The myosin-head domain is particularly significant, as it contains the actin-binding regions (amino acids 655-667 and 757-771) and is responsible for the protein’s contractile power. The myosin-tail domain ensures the proper attachment of myosin to the sarcomere. Within this domain, four specific amino acids, known as “skip” residues (Thr1188, Glu1385, Glu1582, and Gly1807), disrupt the repetitive sequence. These skips modify the coiled-coil structure in their surroundings, with the last skip playing a crucial role in myosin incorporation into the sarcomere structure.10Figure 2 highlights the structure of MYH7.

– Schema of the MYH7 gene highlighting key structural subunits and functional domains

Pathogenic variants in MYH7: clinical implications

Numerous genetic variants affecting MYH7 have been documented in the medical literature and have been associated with a variety of phenotypes, including CHD (primarily cardiomyopathies and some congenital disorders such as Ebstein anomaly) and skeletal myopathies. The mechanisms leading to these diverse phenotypes are not yet fully understood. Analysis of variants reported in public databases of genetic variation (e.g., ClinVar, DECIPHER, GnomAD) suggests that loss-of-function variants may not be disease-causing for this gene. In 2018, the ClinGen Hereditary Cardiomyopathy Expert Panel adapted the ACMG/AMP Variant Classification Criteria specifically targeting MYH7 variants in cardiomyopathies. The panel downgraded the PVS1 criteria (predicted null variant in a gene where loss of function is a known disease mechanism) to moderate strength due to the lack of sufficient evidence linking such variants to CHD.12,13 The predominant type of disease-causing variants in MYH7 are missense mutations, particularly clustered in amino acids 167–931, which largely overlap the myosin head domain. This region exhibits a statistically significant clustering of pathogenic variants.13

 Genotype-phenotype correlation Correlating MYH7 variants with cardiomyopathy phenotypes

The MYH7 gene encodes the beta-myosin heavy chain, a protein expressed in both cardiac and skeletal muscle cells. Genetic variants in MYH7 can lead to a wide array of phenotypes, encompassing various forms of cardiomyopathies and skeletal myopathies14 (Central Illustration).

 MYH7-related hypertrophic cardiomyopathy: Genetic drivers and clinical presentation

HCM is an inherited cardiac disease characterized by hypertrophy of the left ventricular wall, which may extend into the right ventricle. This occurs in the absence of other conditions that can cause pressure overload, such as hypertension or aortic stenosis, or conditions that lead to thickening of the ventricular wall, such as Fabry disease or cardiac amyloidosis.6 In the United States, the prevalence of HCM with an overt phenotype is approximately 1 in 500 individuals. This prevalence increases to 1 in 200 when individuals with both a positive genotype and a negative phenotype are included.4,15 Diagnosis relies primarily on imaging techniques, such as echocardiography or cardiac magnetic resonance imaging.6,16 HCM is characterized by myocardial dislocation that leads to sarcomere hypertrophy and symptoms including dyspnea, chest pain, palpitations, and sudden death.17,18 The disease usually follows an autosomal dominant pattern of inheritance, although some cases result from de novo mutations.19 MYH7 variants are associated with severe phenotypes, including atrial fibrillation, ventricular arrhythmias, conduction system disorders, and earlier age at diagnosis.15,17 Genetic testing, typically conducted using panels that include MYH7 and other sarcomeric genes, has a diagnostic yield ranging from 30% in sporadic cases to 60% in familial cases.5,16 Approximately 181 missense variants in MYH7 are classified as “likely pathogenic” or “pathogenic” for HCM in ClinVar.14 Furthermore, recent evidence links specific variants to expected phenotypes in HCM15,17 (Figure 3).

– Impact of the Presence of Sarcomeric Variant on the HCM Phenotype. HCM: Hypertrophic cardiomyopathy; LVOTO: left ventricular outflow tract obstruction; SDR: sudden death rate.

MYH7-Related dilated cardiomyopathy: Pathogenesis and phenotypic expression

DCM is characterized by left ventricular dilation and systolic dysfunction, defined by an ejection fraction below 50%.6 This condition cannot be solely attributed to valvular heart diseases, systemic hypertension, or coronary artery disease.6 Various factors, including viral infections, alcohol abuse, and anabolic steroid use, can contribute to DCM, along with genetic variants that may act independently or within a multifactorial context.6 DCM often represents the end pathway for various cardiomyopathies.18

Etiologically, DCM can be divided into genetic and non-genetic causes. Non-genetic causes include myocarditis (from viruses, bacteria, fungi, parasites); toxins (e.g., alcohol, cocaine, amphetamines, anabolic steroids, hemochromatosis); endocrine disorders (hypo/hyperthyroidism, Cushing’s syndrome, pheochromocytoma, acromegaly, diabetes mellitus); nutritional deficiencies (selenium, thiamine, zinc, copper, carnitine); electrolyte disturbances (hypocalcemia, hypophosphatemia); peripartum conditions; autoimmune diseases (giant cell myocarditis, eosinophilic granulomatosis with polyangiitis, systemic lupus erythematosus, sarcoidosis, rheumatoid arthritis, celiac disease, inflammatory bowel diseases); and medications (chemotherapeutics, psychiatric medications, antiretrovirals).6

Pathogenic or likely pathogenic genetic variants are present in approximately 20-40% of familial DCM cases and 15-25% of unselected DCM cases.20 The most commonly associated genes include LMNA, MYH7, TNNT2, TTN, RBM20, and BAG3.21-25 Most genetic variants related to DCM follow an autosomal dominant inheritance pattern, although autosomal recessive, X-linked, and mitochondrial inheritance modes have also been reported.26,27

MYH7 is the third most frequently associated gene with DCM.22 Most variants in this gene are non-truncated and exhibit high penetrance in familial cases, with a significant proportion of pediatric patients.28-30 Approximately 59 missense variants and three loss-of-function variants in MYH7 are classified as “likely pathogenic” or “pathogenic” for DCM in ClinVar.14 The pathogenic mechanism of MYH7 variants in DCM contrasts with that in HCM, involving reduced sarcomeric contractility due to impaired ATPase activity and decreased sliding velocity along actin filaments.31,32 This leads to ventricular dilation and cardiac remodeling.31,32

 MYH7-related restrictive cardiomyopathy: Genetic underpinnings and clinical features

RCM is characterized by restrictive ventricular physiology with normal or reduced systolic and diastolic diameters, preserved left ventricular ejection fraction, and normal ventricular wall thickness.6 Biatrial dilation is commonly observed, even with normally sized ventricles.6 RCM often represents an early stage of certain diseases and may progress to DCM.6

Causes of RCM are divided into two main categories:

Intrinsic myocardial dysfunction: Includes genetic cardiomyopathies (e.g., sarcomeric variants, filamin A, titin); storage diseases (e.g., Fabry disease, Danon disease, glycogen storage diseases, PRKAG2 syndrome, hemochromatosis); and medications (e.g., hydroxychloroquine).6,33

Extracellular matrix disorders: Includes infiltrative diseases (e.g., amyloidosis, sarcoidosis, hyperoxaluria) and fibrotic diseases (e.g., radiation, chemotherapy, systemic sclerosis, diabetic cardiomyopathy).6,33

It is essential to differentiate RCM from endocardial diseases that present restrictive physiology, such as endomyocardial fibrosis, hypereosinophilia, carcinoid syndrome, neoplasms, and radiation-induced conditions.6,33

Familial RCM is typically inherited in an autosomal dominant manner.34 The primary genes involved include TNNI3, TNNT2, ACTC1, and MYH7.34 In some cases, familial RCM may be associated with conduction defects resulting from variants in the DES gene, often accompanied by skeletal myopathy.34 Other less common inheritance patterns include autosomal recessive (e.g., variants in HFE and PRKAG2) and X-linked inheritance (e.g., Anderson-Fabry disease).34

Specifically, MYH7-related RCM variants are predominantly autosomal dominant and missense in nature.34 In the ClinVar database, two missense variants are classified as “pathogenic” or “likely pathogenic” with high confidence, supported by multiple references.14

 MYH7 and left ventricular hypertrabeculation (LVHT): A controversial phenotype

LVHT, previously known as noncompaction of the myocardium, remains a controversial topic, with some experts classifying it as a genetic cardiomyopathy and others viewing excessive trabeculation as a morphological feature present in several pathological processes and therefore not constituting a distinct disease.35 The main feature of LVHT is the presence of prominent trabeculae in the left ventricle and deep intertrabecular recesses that are continuous with the LV cavity and distinct from the epicardial coronary arteries.35

Variants associated with LVHT involve a diverse array of proteins, including those related to the sarcomere, cytoskeleton, mitochondria, desmosomes, storage, and ion channels, all of which have been implicated in different cardiac diseases.36 Approximately one-third of LVHT cases involve a pathogenic variant, with the majority following an autosomal dominant inheritance pattern.37 The most frequently implicated genes include MYH7, MYBPC3, ACTC1, TTN, LMNA, RBM20, ACTN2, and PRDM16, although these genes are not unique to LVHT.35,37 Unlike HCM and DCM, truncating variants in MYH7 are considered pathogenic in LVHT.38 In ClinVar, seven missense variants and four loss-of-function variants in MYH7 are classified as “pathogenic” or “likely pathogenic.”14 Patients with LVHT and MYH7 variants generally have a lower risk of adverse cardiovascular events when compared to those with variants of other genes.39

 Expanding the MYH7 spectrum: Skeletal myopathies and other phenotypic associations

Patients with MYH7 variants can present a wide range of clinical phenotypes, including isolated cardiomyopathy, isolated skeletal muscle myopathy, or a combination of both.40 While this review focuses on cardiomyopathies, MYH7-related skeletal muscle diseases are predominantly autosomal dominant and can manifest from childhood to adulthood, exhibiting considerable clinical and prognostic variability.41 The main skeletal myopathies associated with MYH7 include Laing distal myopathy, myosin storage myopathy, congenital myopathy with fiber-type disproportion, and MYH7-related late-onset scapuloperoneal muscular dystrophy.14

Additionally, MYH7 appears to play a role in tumorigenesis. In patients with smoking-associated lung adenocarcinoma, 12% harbor MYH7 variants, which are associated with cancer progression and poorer prognosis.42 MYH7 has also been linked to prostate cancer, oral cancer, and Epstein-Barr virus-associated intrahepatic cholangiocarcinoma.43-45 Both “pathogenic” or “possibly pathogenic” variants and alterations in gene expression can influence cancer onset and progression.41-45

 Prognostic factors and clinical implications of MYH7 variants in cardiomyopathies

Beyond the diverse phenotypic associations, various studies have identified significant prognostic factors related to MYH7 variants (Figure 4). A Dutch multicenter cohort study, involving 581 individuals (30.1% index patients, 48.4% male, median age 37 years) diagnosed with HCM, LVHT, or DCM, found that early penetrance and major cardiovascular events (MACE) were more prevalent in carriers of MYH7 variants associated with LVHT and DCM compared with those with HCM. Specifically, MACE occurred in 21.2% and 12.0% of LVHT and DCM carriers, respectively, versus 2.9% and 2.1% of HCM carriers.46 The risk of MACE was significantly higher in individuals with a family history of early MACE (adjusted HR: 1.82; 95% CI: 1.15-2.87; p = 0.010) or those with LVHT or DCM phenotypes diagnosed at ≤5 years of age (adjusted HR: 38.82; 95% CI: 5.16-291.88; p < 0.001).46 These findings suggest the need for early screening, especially for carriers of LVHT or DCM-associated variants, as well as those with a family history of MACE before age 12 years. 46Another multicenter cohort study with a median follow-up of 4.5 years examined 147 patients with MYH7 variants associated with DCM, of whom 72.1% had DCM at baseline. 47 During follow-up, 23.7% of initially phenotype-negative carriers developed DCM, and 28% exhibited reverse left ventricular remodeling. 47 The incidence of MACE at 5 years was 11.6%, including five deaths from advanced heart failure and five heart transplants. 47 The incidence of ventricular arrhythmias was low (1% at 5 years, increasing to 5% with LVEF ≤35%), which is lower when compared with DCM associated with LMNA gene variants. 47

– Prognostic factors of MYH7 cardiomyopathies. MACE: major cardiovascular events.

The type of MYH7 variant also influences clinical outcomes. A case series reported that the MYH7 R453C and R453H variants were associated with severe HCM phenotypes requiring advanced heart failure interventions. 48 Missense variants in MYH7 relevant to the development of HCM are predominantly located in the S1 and S2 regions of the gene. 49 Recent studies have confirmed that variants in the converter domain and residues within the myosin “table” are common sites for HCM-associated MYH7 variants, which tend to appear earlier, progress more rapidly, and overlap with other phenotypes, compared with variants in other regions of the gene.50

Furthermore, the cumulative effect of multiple MYH7 variants exacerbates the severity of HCM, leading to an earlier onset, a higher risk of sudden cardiac death (SCD), and a poorer prognosis.51-63 A mouse model demonstrated this additive effect: mice with a single missense variant (p.Val606Met) exhibited a relatively benign phenotype, whereas mice with double pathogenic variants (p.V606M & p.R453C or p.V606M & p.R719W) developed a more pronounced hypertrophic phenotype.64

 Conclusion

MYH7 is a sarcomeric gene essential for the pathophysiology of cardiomyopathies, particularly HCM and DCM, and contributes to less common phenotypes such as CMR and LVHT. In addition, certain MYH7 variants are associated with skeletal myopathies, sometimes overlapping with cardiomyopathies. Advances in the understanding of MYH7 genetic variants and their functional impacts have significantly increased our knowledge of the molecular mechanisms underlying these conditions.

Integrating genetic diagnosis with clinical assessment is essential for effective patient management, enabling a personalized approach that considers both genetic profiles and individual clinical manifestations. Emerging technologies, including gene editing and molecular therapies, promise more targeted and effective interventions. The success of these approaches depends on continued collaboration between cardiologists, geneticists, and researchers, emphasizing the importance of clinical practice aligned with robust genetic discoveries.

Looking ahead, the management of MYH7-associated cardiomyopathies and related genetic conditions will increasingly rely on the intersection of cutting-edge genetic research and meticulous clinical application. This integration aims to improve patient outcomes and quality of life through personalized medicine and advanced therapeutic strategies.

 References 1. Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, et al. The Landscape of Genetic Variation in Dilated Cardiomyopathy as Surveyed by Clinical DNA Sequencing. Genet Med. 2014;16(8):601-8. doi: 10.1038/gim.2013.204. Pugh TJ Kelly MA Gowrisankar S Hynes E Seidman MA Baxter SM et al The Landscape of Genetic Variation in Dilated Cardiomyopathy as Surveyed by Clinical DNA Sequencing Genet Med 2014 16 8 601 608 10.1038/gim.2013.204 2. Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, et al. Results of Clinical Genetic Testing of 2,912 Probands with Hypertrophic Cardiomyopathy: Expanded Panels Offer Limited Additional Sensitivity. Genet Med. 2015;17(11):880-8. doi: 10.1038/gim.2014.205. Alfares AA Kelly MA McDermott G Funke BH Lebo MS Baxter SB et al Results of Clinical Genetic Testing of 2,912 Probands with Hypertrophic Cardiomyopathy: Expanded Panels Offer Limited Additional Sensitivity Genet Med 2015 17 11 880 888 10.1038/gim.2014.205 3. Semsarian C, Ingles J, Maron MS, Maron BJ. New Perspectives on the Prevalence of Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2015;65(12):1249-54. doi: 10.1016/j.jacc.2015.01.019. Semsarian C Ingles J Maron MS Maron BJ New Perspectives on the Prevalence of Hypertrophic Cardiomyopathy J Am Coll Cardiol 2015 65 12 1249 1254 10.1016/j.jacc.2015.01.019 4. Ho CY, Day SM, Ashley EA, Michels M, Pereira AC, Jacoby D, et al. Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation. 2018;138(14):1387-98. doi: 10.1161/CIRCULATIONAHA.117.033200. Ho CY Day SM Ashley EA Michels M Pereira AC Jacoby D et al Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe) Circulation 2018 138 14 1387 1398 10.1161/CIRCULATIONAHA.117.033200 5. Furquim SR, Lipari LFVP, Andrade FA, Correia VM, Olivetti NQS, Pires LVL, et al. Genetic Testing in Cardiomyopathy: Decoding Molecular Underpinnings and Influencing Treatment Decisions. Int J Cardiovasc Sci. 2024;37:e20230153. doi: 10.36660/ijcs.20230153. Furquim SR Lipari LFVP Andrade FA Correia VM Olivetti NQS Pires LVL et al Genetic Testing in Cardiomyopathy: Decoding Molecular Underpinnings and Influencing Treatment Decisions Int J Cardiovasc Sci 2024 37 e20230153 10.36660/ijcs.20230153 6. Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, et al. 2023 ESC Guidelines for the Management of Cardiomyopathies. Eur Heart J. 2023;44(37):3503-626. doi: 10.1093/eurheartj/ehad194. Arbelo E Protonotarios A Gimeno JR Arbustini E Barriales-Villa R Basso C et al 2023 ESC Guidelines for the Management of Cardiomyopathies Eur Heart J 2023 44 37 3503 3626 10.1093/eurheartj/ehad194 7. Kayvanpour E, Sedaghat-Hamedani F, Gi WT, Tugrul OF, Amr A, Haas J, et al. Clinical and Genetic Insights Into Non-Compaction: A Meta-Analysis and Systematic Review on 7598 Individuals. Clin Res Cardiol. 2019;108(11):1297-308. doi: 10.1007/s00392-019-01465-3. Kayvanpour E Sedaghat-Hamedani F Gi WT Tugrul OF Amr A Haas J et al Clinical and Genetic Insights Into Non-Compaction: A Meta-Analysis and Systematic Review on 7598 Individuals Clin Res Cardiol 2019 108 11 1297 1308 10.1007/s00392-019-01465-3 8. Jaenicke T, Diederich KW, Haas W, Schleich J, Lichter P, Pfordt M, et al. The Complete Sequence of the Human Beta-Myosin Heavy Chain Gene and a Comparative Analysis of its Product. Genomics. 1990;8(2):194-206. doi: 10.1016/0888-7543(90)90272-v. Jaenicke T Diederich KW Haas W Schleich J Lichter P Pfordt M et al The Complete Sequence of the Human Beta-Myosin Heavy Chain Gene and a Comparative Analysis of its Product Genomics 1990 8 2 194 206 10.1016/0888-7543(90)90272-v 9. Liew CC, Sole MJ, Yamauchi-Takihara K, Kellam B, Anderson DH, Lin LP, et al. Complete Sequence and Organization of the Human Cardiac Beta-Myosin Heavy Chain Gene. Nucleic Acids Res. 1990;18(12):3647-51. doi: 10.1093/nar/18.12.3647. Liew CC Sole MJ Yamauchi-Takihara K Kellam B Anderson DH Lin LP et al Complete Sequence and Organization of the Human Cardiac Beta-Myosin Heavy Chain Gene Nucleic Acids Res 1990 18 12 3647 3651 10.1093/nar/18.12.3647 10. Taylor KC, Buvoli M, Korkmaz EN, Buvoli A, Zheng Y, Heinze NT, et al. Skip Residues Modulate the Structural Properties of the Myosin Rod and Guide Thick Filament Assembly. Proc Natl Acad Sci U S A. 2015;112(29):E3806-15. doi: 10.1073/pnas.1505813112. Taylor KC Buvoli M Korkmaz EN Buvoli A Zheng Y Heinze NT et al Skip Residues Modulate the Structural Properties of the Myosin Rod and Guide Thick Filament Assembly Proc Natl Acad Sci U S A 2015 112 29 E3806 E3815 10.1073/pnas.1505813112 11. Korkmaz EN, Taylor KC, Andreas MP, Ajay G, Heinze NT, Cui Q, et al. A Composite Approach Towards a Complete Model of the Myosin Rod. Proteins. 2016;84(1):172-89. doi: 10.1002/prot.24964. Korkmaz EN Taylor KC Andreas MP Ajay G Heinze NT Cui Q et al A Composite Approach Towards a Complete Model of the Myosin Rod Proteins 2016 84 1 172 189 10.1002/prot.24964 12. Kelly MA, Caleshu C, Morales A, Buchan J, Wolf Z, Harrison SM, et al. Adaptation and Validation of the ACMG/AMP Variant Classification Framework for MYH7-Associated Inherited Cardiomyopathies: Recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel. Genet Med. 2018;20(3):351-9. doi: 10.1038/gim.2017.218. Kelly MA Caleshu C Morales A Buchan J Wolf Z Harrison SM et al Adaptation and Validation of the ACMG/AMP Variant Classification Framework for MYH7-Associated Inherited Cardiomyopathies: Recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel Genet Med 2018 20 3 351 359 10.1038/gim.2017.218 13. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24. doi: 10.1038/gim.2015.30. Richards S Aziz N Bale S Bick D Das S Gastier-Foster J et al Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genet Med 2015 17 5 405 424 10.1038/gim.2015.30 14. Gao Y, Peng L, Zhao C. MYH7 in Cardiomyopathy and Skeletal Muscle Myopathy. Mol Cell Biochem. 2024;479(2):393-417. doi: 10.1007/s11010-023-04735-x. Gao Y Peng L Zhao C MYH7 in Cardiomyopathy and Skeletal Muscle Myopathy Mol Cell Biochem 2024 479 2 393 417 10.1007/s11010-023-04735-x 15. Fernandes F, Simões MV, Correia EB, Marcondes-Braga FG, Coelho-Filho OR, Mesquita CT, et al. Guidelines on the Diagnosis and Treatment of Hypertrophic Cardiomyopathy - 2024. Arq Bras Cardiol. 2024:121(7): e202400415. doi: 10.36660/abc.20240415i. Fernandes F Simões MV Correia EB Marcondes-Braga FG Coelho-Filho OR Mesquita CT et al Guidelines on the Diagnosis and Treatment of Hypertrophic Cardiomyopathy - 2024 Arq Bras Cardiol 2024 121 7 e202400415 10.36660/abc.20240415i 16. Ommen SR, Ho CY, Asif IM, Balaji S, Burke MA, Day SM, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(23):e1239-e1311. doi: 10.1161/CIR.0000000000001250. Ommen SR Ho CY Asif IM Balaji S Burke MA Day SM et al 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines Circulation 2024 149 23 e1239 e1311 10.1161/CIR.0000000000001250 17. Toste A. Advances in Hypertrophic Cardiomyopathy: What the Cardiologist Needs to Know. Rev Port Cardiol. 2022;41(6):499-509. doi: 10.1016/j.repc.2021.05.015. Toste A Advances in Hypertrophic Cardiomyopathy: What the Cardiologist Needs to Know Rev Port Cardiol 2022 41 6 499 509 10.1016/j.repc.2021.05.015 18. Schultheiss HP, Fairweather D, Caforio ALP, Escher F, Hershberger E, Lipshultz SE, et al. Dilated Cardiomyopathy. Nat Rev Dis Primers. 2019;5(1):32. doi: 10.1038/s41572-019-0084-1. Schultheiss HP Fairweather D Caforio ALP Escher F Hershberger E Lipshultz SE et al Dilated Cardiomyopathy Nat Rev Dis Primers 2019 5 1 32 10.1038/s41572-019-0084-1 19. Maron BJ. Clinical Course and Management of Hypertrophic Cardiomyopathy. N Engl J Med. 2018;379(7):655-68. doi: 10.1056/NEJMra1710575. Maron BJ Clinical Course and Management of Hypertrophic Cardiomyopathy N Engl J Med 2018 379 7 655 668 10.1056/NEJMra1710575 20. Correia VM, Oliveira LH, Madrini V Jr, Rocha RG, Leguizamon JAGO, Costa LMA, et al. Dilated Cardiomyopathy: A New Era of Treatment. Cardiol Cardiovasc Med. 2024;8(4):362-78. doi: 10.26502/fccm.92920397. Correia VM Oliveira LH Madrini V Jr Rocha RG Leguizamon JAGO Costa LMA et al Dilated Cardiomyopathy: A New Era of Treatment Cardiol Cardiovasc Med 2024 8 4 362 378 10.26502/fccm.92920397 21. Fatkin D, MacRae C, Sasaki T, Wolff MR, Porcu M, Frenneaux M, et al. Missense Mutations in the Rod Domain of the Lamin A/C Gene as Causes of Dilated Cardiomyopathy and Conduction-System Disease. N Engl J Med. 1999;341(23):1715-24. doi: 10.1056/NEJM199912023412302. Fatkin D MacRae C Sasaki T Wolff MR Porcu M Frenneaux M et al Missense Mutations in the Rod Domain of the Lamin A/C Gene as Causes of Dilated Cardiomyopathy and Conduction-System Disease N Engl J Med 1999 341 23 1715 1724 10.1056/NEJM199912023412302 22. Kamisago M, Sharma SD, De Palma SR, Solomon S, Sharma P, Mc Donough B, et al. Mutations in Sarcomere Protein Genes as a Cause of Dilated Cardiomyopathy. N Engl J Med. 2000;343(23):1688-96. doi: 10.1056/NEJM200012073432304. Kamisago M Sharma SD De Palma SR Solomon S Sharma P Mc Donough B et al Mutations in Sarcomere Protein Genes as a Cause of Dilated Cardiomyopathy N Engl J Med 2000 343 23 1688 1696 10.1056/NEJM200012073432304 23. Gerull B, Gramlich M, Atherton J, Mc Nabb M, Trombitás K, Sasse-Klaassen S, et al. Mutations of TTN, Encoding the Giant Muscle Filament Titin, Cause Familial Dilated Cardiomyopathy. Nat Genet. 2002;30(2):201-4. doi: 10.1038/ng815. Gerull B Gramlich M Atherton J Mc Nabb M Trombitás K Sasse-Klaassen S et al Mutations of TTN, Encoding the Giant Muscle Filament Titin, Cause Familial Dilated Cardiomyopathy Nat Genet 2002 30 2 201 204 10.1038/ng815 24. Brauch KM, Karst ML, Herron KJ, Andrade M, Pellikka PA, Rodeheffer RJ, et al. Mutations in Ribonucleic acid Binding Protein Gene Cause Familial Dilated Cardiomyopathy. J Am Coll Cardiol. 2009;54(10):930-41. doi: 10.1016/j.jacc.2009.05.038. Brauch KM Karst ML Herron KJ Andrade M Pellikka PA Rodeheffer RJ et al Mutations in Ribonucleic acid Binding Protein Gene Cause Familial Dilated Cardiomyopathy J Am Coll Cardiol 2009 54 10 930 941 10.1016/j.jacc.2009.05.038 25. Norton N, Li D, Rieder MJ, Siegfried JD, Rampersaud E, Züchner S, et al. Genome-Wide Studies of Copy Number Variation and Exome Sequencing Identify Rare Variants in BAG3 as a Cause of Dilated Cardiomyopathy. Am J Hum Genet. 2011;88(3):273-82. doi: 10.1016/j.ajhg.2011.01.016. Norton N Li D Rieder MJ Siegfried JD Rampersaud E Züchner S et al Genome-Wide Studies of Copy Number Variation and Exome Sequencing Identify Rare Variants in BAG3 as a Cause of Dilated Cardiomyopathy Am J Hum Genet 2011 88 3 273 282 10.1016/j.ajhg.2011.01.016 26. Hershberger RE, Hedges DJ, Morales A. Dilated Cardiomyopathy: The Complexity of a Diverse Genetic Architecture. Nat Rev Cardiol. 2013;10:531-47. doi:10.1038/nrcardio.2013.105. Hershberger RE Hedges DJ Morales A Dilated Cardiomyopathy: The Complexity of a Diverse Genetic Architecture Nat Rev Cardiol 2013 10 531 547 10.1038/nrcardio.2013.105 27. Mestroni L, Maisch B, Mc Kenna WJ, Schwartz K, Charron P, Tesson F, et al. Guidelines for the Study of Familial Dilated Cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy. Eur Heart J. 1999;20(2):93-102. doi: 10.1053/euhj.1998.1145. Mestroni L Maisch B Mc Kenna WJ Schwartz K Charron P Tesson F et al Guidelines for the Study of Familial Dilated Cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy Eur Heart J 1999 20 2 93 102 10.1053/euhj.1998.1145 28. Mazzarotto F, Tayal U, Buchan RJ, Midwinter W, Wilk A, Whiffin N, et al. Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy. Circulation. 2020;141(5):387-98. doi: 10.1161/CIRCULATIONAHA.119.037661. Mazzarotto F Tayal U Buchan RJ Midwinter W Wilk A Whiffin N et al Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy Circulation 2020 141 5 387 398 10.1161/CIRCULATIONAHA.119.037661 29. Jordan E, Peterson L, Ai T, Asatryan B, Bronicki L, Brown E, et al. Evidence-Based Assessment of Genes in Dilated Cardiomyopathy. Circulation. 2021;144(1):7-19. doi: 10.1161/CIRCULATIONAHA.120.053033. Jordan E Peterson L Ai T Asatryan B Bronicki L Brown E et al Evidence-Based Assessment of Genes in Dilated Cardiomyopathy Circulation 2021 144 1 7 19 10.1161/CIRCULATIONAHA.120.053033 30. Lanfear DE, Reza N. Myosin-Related Dilated Cardiomyopathy: Another Elephant Emerges from Darkness. J Am Coll Cardiol. 2022;80(15):1462-4. doi: 10.1016/j.jacc.2022.08.749. Lanfear DE Reza N Myosin-Related Dilated Cardiomyopathy: Another Elephant Emerges from Darkness J Am Coll Cardiol 2022 80 15 1462 1464 10.1016/j.jacc.2022.08.749 31. Debold EP, Schmitt JP, Patlak JB, Beck SE, Moore JR, Seidman JG, et al. Hypertrophic and Dilated Cardiomyopathy Mutations Differentially Affect the Molecular Force Generation of Mouse Alpha-Cardiac Myosin in the Laser Trap Assay. Am J Physiol Heart Circ Physiol. 2007;293(1):H284-91. doi: 10.1152/ajpheart.00128.2007. Debold EP Schmitt JP Patlak JB Beck SE Moore JR Seidman JG et al Hypertrophic and Dilated Cardiomyopathy Mutations Differentially Affect the Molecular Force Generation of Mouse Alpha-Cardiac Myosin in the Laser Trap Assay Am J Physiol Heart Circ Physiol 2007 293 1 H284 H291 10.1152/ajpheart.00128.2007 32. Schmitt JP, Debold EP, Ahmad F, Armstrong A, Frederico A, Conner DA, et al. Cardiac Myosin Missense Mutations Cause Dilated Cardiomyopathy in Mouse Models and Depress Molecular Motor Function. Proc Natl Acad Sci USA. 2006;103(39):14525-30. doi: 10.1073/pnas.0606383103. Schmitt JP Debold EP Ahmad F Armstrong A Frederico A Conner DA et al Cardiac Myosin Missense Mutations Cause Dilated Cardiomyopathy in Mouse Models and Depress Molecular Motor Function Proc Natl Acad Sci USA 2006 103 39 14525 14530 10.1073/pnas.0606383103 33. Madan N, Kalra D. Clinical Evaluation of Infiltrative Cardiomyopathies Resulting in Heart Failure with Preserved Ejection Fraction. Rev Cardiovasc Med. 2020;21(2):181-90. doi: 10.31083/j.rcm.2020.02.65. Madan N Kalra D Clinical Evaluation of Infiltrative Cardiomyopathies Resulting in Heart Failure with Preserved Ejection Fraction Rev Cardiovasc Med 2020 21 2 181 190 10.31083/j.rcm.2020.02.65 34. Muchtar E, Blauwet LA, Gertz MA. Restrictive Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy. Circ Res. 2017;121(7):819-37. doi:10.1161/CIRCRESAHA.117.310982. Muchtar E Blauwet LA Gertz MA Restrictive Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy Circ Res 2017 121 7 819 837 doi:10.1161/CIRCRESAHA.117.310982 35. Correia VM, Madrini V Jr, Ramires FJA. Uncompacted Myocardium: A Disease or a Phenotype? ABC Heart Fail Cardiomyop. 2023;3(1):e20230047. doi: 10.36660/abchf.20230047. Correia VM Madrini V Jr Ramires FJA Uncompacted Myocardium: A Disease or a Phenotype? ABC Heart Fail Cardiomyop 2023 3 1 e20230047 10.36660/abchf.20230047 36. D'Silva A, Jensen B. Left Ventricular Non-Compaction Cardiomyopathy: How Many Needles in the Haystack? Heart. 2021;107(16):1344-52. doi: 10.1136/heartjnl-2020-316945. D'Silva A Jensen B Left Ventricular Non-Compaction Cardiomyopathy: How Many Needles in the Haystack? Heart 2021 107 16 1344 1352 10.1136/heartjnl-2020-316945 37. Petersen SE, Jensen B, Aung N, Friedrich MG, Mc Mahon CJ, Mohiddin SA, et al. Excessive Trabeculation of the Left Ventricle: JACC: Cardiovascular Imaging Expert Panel Paper. JACC Cardiovasc Imaging. 2023;16(3):408-25. doi: 10.1016/j.jcmg.2022.12.026. Petersen SE Jensen B Aung N Friedrich MG Mc Mahon CJ Mohiddin SA et al Excessive Trabeculation of the Left Ventricle: JACC: Cardiovascular Imaging Expert Panel Paper JACC Cardiovasc Imaging 2023 16 3 408 425 10.1016/j.jcmg.2022.12.026 38. Klaassen S, Probst S, Oechslin E, Gerull B, Krings G, Schuler P, et al. Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction. Circulation. 2008;117(22):2893-901. doi: 10.1161/CIRCULATIONAHA.107.746164. Klaassen S Probst S Oechslin E Gerull B Krings G Schuler P et al Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction Circulation 2008 117 22 2893 2901 10.1161/CIRCULATIONAHA.107.746164 39. van Waning JI, Caliskan K, Hoedemaekers YM, van Spaendonck-Zwarts KY, Baas AF, Boekholdt SM, et al. Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy. J Am Coll Cardiol. 2018;71(7):711-22. doi: 10.1016/j.jacc.2017.12.019. van Waning JI Caliskan K Hoedemaekers YM van Spaendonck-Zwarts KY Baas AF Boekholdt SM et al Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy J Am Coll Cardiol 2018 71 7 711 722 10.1016/j.jacc.2017.12.019 40. Fiorillo C, Astrea G, Savarese M, Cassandrini D, Brisca G, Trucco F, et al. MYH7-Related Myopathies: Clinical, Histopathological and Imaging Findings in a Cohort of Italian Patients. Orphanet J Rare Dis. 2016;11(1):91. doi: 10.1186/s13023-016-0476-1. Fiorillo C Astrea G Savarese M Cassandrini D Brisca G Trucco F et al MYH7-Related Myopathies: Clinical, Histopathological and Imaging Findings in a Cohort of Italian Patients Orphanet J Rare Dis 2016 11 1 91 10.1186/s13023-016-0476-1 41. Lamont PJ, Udd B, Mastaglia FL, Visser M, Hedera P, Voit T, et al. Laing Early Onset Distal Myopathy: Slow Myosin Defect with Variable Abnormalities on Muscle Biopsy. J Neurol Neurosurg Psychiatry. 2006;77(2):208-15. doi: 10.1136/jnnp.2005.073825. Lamont PJ Udd B Mastaglia FL Visser M Hedera P Voit T et al Laing Early Onset Distal Myopathy: Slow Myosin Defect with Variable Abnormalities on Muscle Biopsy J Neurol Neurosurg Psychiatry 2006 77 2 208 215 10.1136/jnnp.2005.073825 42. Zhang Y, Wang Q, Zhu T, Chen H. Identification of Cigarette Smoking-Related Novel Biomarkers in Lung Adenocarcinoma. Biomed Res Int. 2022;2022:9170722. doi: 10.1155/2022/9170722. Zhang Y Wang Q Zhu T Chen H Identification of Cigarette Smoking-Related Novel Biomarkers in Lung Adenocarcinoma Biomed Res Int 2022 2022 9170722 10.1155/2022/9170722 43. Sun J, Li S, Wang F, Fan C, Wang J. Identification of Key Pathways and Genes in PTEN Mutation Prostate Cancer by Bioinformatics Analysis. BMC Med Genet. 2019;20(1):191. doi: 10.1186/s12881-019-0923-7. Sun J Li S Wang F Fan C Wang J Identification of Key Pathways and Genes in PTEN Mutation Prostate Cancer by Bioinformatics Analysis BMC Med Genet 2019 20 1 191 10.1186/s12881-019-0923-7 44. Mahapatra S, Bhuyan R, Das J, Swarnkar T. Integrated Multiplex Network Based Approach for Hub Gene Identification in Oral Cancer. Heliyon. 2021;7(7):e07418. doi: 10.1016/j.heliyon.2021.e07418. Mahapatra S Bhuyan R Das J Swarnkar T Integrated Multiplex Network Based Approach for Hub Gene Identification in Oral Cancer Heliyon 2021 7 7 e07418 10.1016/j.heliyon.2021.e07418 45. Huang YH, Zhang CZ, Huang QS, Yeong J, Wang F, Yang X, et al. Clinicopathologic Features, Tumor Immune Microenvironment and Genomic Landscape of Epstein-Barr Virus-Associated Intrahepatic Cholangiocarcinoma. J Hepatol. 2021;74(4):838-49. doi: 10.1016/j.jhep.2020.10.037. Huang YH Zhang CZ Huang QS Yeong J Wang F Yang X et al Clinicopathologic Features, Tumor Immune Microenvironment and Genomic Landscape of Epstein-Barr Virus-Associated Intrahepatic Cholangiocarcinoma J Hepatol 2021 74 4 838 849 10.1016/j.jhep.2020.10.037 46. Jansen M, Brouwer R, Hassanzada F, Schoemaker AE, Schmidt AF, Kooijman-Reumerman MD, et al. Penetrance and Prognosis of MYH7 Variant-Associated Cardiomyopathies: Results from a Dutch Multicenter Cohort Study. JACC Heart Fail. 2024;12(1):134-47. doi: 10.1016/j.jchf.2023.07.007. Jansen M Brouwer R Hassanzada F Schoemaker AE Schmidt AF Kooijman-Reumerman MD et al Penetrance and Prognosis of MYH7 Variant-Associated Cardiomyopathies: Results from a Dutch Multicenter Cohort Study JACC Heart Fail 2024 12 1 134 147 10.1016/j.jchf.2023.07.007 47. Frutos F, Ochoa JP, Navarro-Peñalver M, Baas A, Bjerre JV, Zorio E, et al. Natural History of MYH7-Related Dilated Cardiomyopathy. J Am Coll Cardiol. 2022;80(15):1447-61. doi: 10.1016/j.jacc.2022.07.023. Frutos F Ochoa JP Navarro-Peñalver M Baas A Bjerre JV Zorio E et al Natural History of MYH7-Related Dilated Cardiomyopathy J Am Coll Cardiol 2022 80 15 1447 1461 10.1016/j.jacc.2022.07.023 48. Naito S, Higo S, Kameda S, Ogawa S, Tabata T, Akazawa Y, et al. End-stage Hypertrophic Cardiomyopathy with Advanced Heart Failure in Patients Carrying MYH7 R453 Variants: A Case Series. Intern Med. 2023;62(21):3167-73. doi: 10.2169/internalmedicine.1497-22. Naito S Higo S Kameda S Ogawa S Tabata T Akazawa Y et al End-stage Hypertrophic Cardiomyopathy with Advanced Heart Failure in Patients Carrying MYH7 R453 Variants: A Case Series Intern Med 2023 62 21 3167 3173 10.2169/internalmedicine.1497-22 49. Colegrave M, Peckham M. Structural Implications of ß-Cardiac Myosin Heavy Chain Mutations in Human Disease. Anat Rec. 2014;297(9):1670-80. doi: 10.1002/ar.22973. Colegrave M Peckham M Structural Implications of ß-Cardiac Myosin Heavy Chain Mutations in Human Disease Anat Rec 2014 297 9 1670 1680 10.1002/ar.22973 50. Homburger JR, Green EM, Caleshu C, Sunitha MS, Taylor RE, Ruppel KM, et al. Multidimensional Structure-Function Relationships in Human ß-Cardiac Myosin from Population-Scale Genetic Variation. Proc Natl Acad Sci USA. 2016;113(24):6701-6. doi: 10.1073/pnas.1606950113. Homburger JR Green EM Caleshu C Sunitha MS Taylor RE Ruppel KM et al Multidimensional Structure-Function Relationships in Human ß-Cardiac Myosin from Population-Scale Genetic Variation Proc Natl Acad Sci USA 2016 113 24 6701 6706 10.1073/pnas.1606950113 51. Wang B, Guo RQ, Wang J, Yang F, Zuo L, Liu Y, et al. The Cumulative Effects of the MYH7-V878A and CACNA1C-A1594V Mutations in a Chinese Family with Hypertrophic Cardiomyopathy. Cardiology. 2017;138(4):228-37. doi: 10.1159/000478900. Wang B Guo RQ Wang J Yang F Zuo L Liu Y et al The Cumulative Effects of the MYH7-V878A and CACNA1C-A1594V Mutations in a Chinese Family with Hypertrophic Cardiomyopathy Cardiology 2017 138 4 228 237 10.1159/000478900 52. Wang L, Zuo L, Hu J, Shao H, Lei C, Qi W, et al. Dual LQT1 and HCM Phenotypes Associated with Tetrad Heterozygous Mutations in KCNQ1, MYH7, MYLK2, and TMEM70 Genes in a Three-Generation Chinese Family. Europace. 2016;18(4):602-9. doi: 10.1093/europace/euv043. Wang L Zuo L Hu J Shao H Lei C Qi W et al Dual LQT1 and HCM Phenotypes Associated with Tetrad Heterozygous Mutations in KCNQ1, MYH7, MYLK2, and TMEM70 Genes in a Three-Generation Chinese Family Europace 2016 18 4 602 609 10.1093/europace/euv043 53. Rodríguez-López R, García-Planells J, Martínez-Matilla M, Pérez-García C, Banacloy AG, Luján CG, et al. Homozygous Pro1066Arg MYBPC3 Pathogenic Variant in a 26Mb Region of Homozygosity Associated with Severe Hypertrophic Cardiomyopathy in a Patient of an Apparent Non-Consanguineous Family. Life. 2022;12(7):1035. doi: 10.3390/life12071035. Rodríguez-López R García-Planells J Martínez-Matilla M Pérez-García C Banacloy AG Luján CG et al Homozygous Pro1066Arg MYBPC3 Pathogenic Variant in a 26Mb Region of Homozygosity Associated with Severe Hypertrophic Cardiomyopathy in a Patient of an Apparent Non-Consanguineous Family Life 2022 12 7 1035 10.3390/life12071035 54. Hsieh J, Becklin KL, Givens S, Komosa ER, Lloréns JEA, Kamdar F, et al. Myosin Heavy Chain Converter Domain Mutations Drive Early-Stage Changes in Extracellular Matrix Dynamics in Hypertrophic Cardiomyopathy. Front Cell Dev Biol. 2022;10:894635. doi: 10.3389/fcell.2022.894635. Hsieh J Becklin KL Givens S Komosa ER Lloréns JEA Kamdar F et al Myosin Heavy Chain Converter Domain Mutations Drive Early-Stage Changes in Extracellular Matrix Dynamics in Hypertrophic Cardiomyopathy Front Cell Dev Biol 2022 10 894635 10.3389/fcell.2022.894635 55. Richard P, Isnard R, Carrier L, Dubourg O, Donatien Y, Mathieu B, et al. Double Heterozygosity for Mutations in the Beta-Myosin Heavy Chain and in the Cardiac Myosin Binding Protein C Genes in a Family with Hypertrophic Cardiomyopathy. J Med Genet. 1999;36(7):542-5. Richard P Isnard R Carrier L Dubourg O Donatien Y Mathieu B et al Double Heterozygosity for Mutations in the Beta-Myosin Heavy Chain and in the Cardiac Myosin Binding Protein C Genes in a Family with Hypertrophic Cardiomyopathy J Med Genet 1999 36 7 542 545 56. Suzuki T, Saito K, Yoshikawa T, Hirono K, Hata Y, Nishida N, et al. A Double Heterozygous Variant in MYH6 and MYH7 Associated with Hypertrophic Cardiomyopathy in a Japanese Family. J Cardiol Cases. 2021;25(4):213-7. doi: 10.1016/j.jccase.2021.09.011. Suzuki T Saito K Yoshikawa T Hirono K Hata Y Nishida N et al A Double Heterozygous Variant in MYH6 and MYH7 Associated with Hypertrophic Cardiomyopathy in a Japanese Family J Cardiol Cases 2021 25 4 213 217 10.1016/j.jccase.2021.09.011 57. Hougs L, Havndrup O, Bundgaard H, Køber L, Vuust J, Larsen LA, et al. One Third of Danish Hypertrophic Cardiomyopathy Patients with MYH7 Mutations have Mutations [corrected] in MYH7 Rod Region. Eur J Hum Genet. 2005;13(2):161-5. doi: 10.1038/sj.ejhg.5201310. Hougs L Havndrup O Bundgaard H Køber L Vuust J Larsen LA et al One Third of Danish Hypertrophic Cardiomyopathy Patients with MYH7 Mutations have Mutations [corrected] in MYH7 Rod Region Eur J Hum Genet 2005 13 2 161 165 10.1038/sj.ejhg.5201310 58. Rani DS, Nallari P, Dhandapany PS, Rani J, Meraj K, Ganesan M, et al. Coexistence of Digenic Mutations in Both Thin (TPM1) and Thick (MYH7) Filaments of Sarcomeric Genes Leads to Severe Hypertrophic Cardiomyopathy in a South Indian FHCM. DNA Cell Biol. 2015;34(5):350-9. doi: 10.1089/dna.2014.2650. Rani DS Nallari P Dhandapany PS Rani J Meraj K Ganesan M et al Coexistence of Digenic Mutations in Both Thin (TPM1) and Thick (MYH7) Filaments of Sarcomeric Genes Leads to Severe Hypertrophic Cardiomyopathy in a South Indian FHCM DNA Cell Biol 2015 34 5 350 359 10.1089/dna.2014.2650 59. Kolokotronis K, Kühnisch J, Klopocki E, Dartsch J, Rost S, Huculak C, et al. Biallelic Mutation in MYH7 and MYBPC3 Leads to Severe Cardiomyopathy with Left Ventricular Noncompaction Phenotype. Hum Mutat. 2019;40:1101-14. doi:10.1002/humu.23757. Kolokotronis K Kühnisch J Klopocki E Dartsch J Rost S Huculak C et al Biallelic Mutation in MYH7 and MYBPC3 Leads to Severe Cardiomyopathy with Left Ventricular Noncompaction Phenotype Hum Mutat 2019 40 1101 1114 10.1002/humu.23757 60. Hershkovitz T, Kurolap A, Ruhrman-Shahar N, Monakier D, DeChene ET, Peretz-Amit G, et al. Clinical Diversity of MYH7-Related Cardiomyopathies: Insights into Genotype-Phenotype Correlations. Am J Med Genet A. 2019;179:365-72. doi:10.1002/ajmg.a.61017. Hershkovitz T Kurolap A Ruhrman-Shahar N Monakier D DeChene ET Peretz-Amit G et al Clinical Diversity of MYH7-Related Cardiomyopathies: Insights into Genotype-Phenotype Correlations Am J Med Genet A 2019 179 365 372 10.1002/ajmg.a.61017 61. Hirono K, Hata Y, Ibuki K, Yoshimura N. Familial Ebstein's Anomaly, Left Ventricular Noncompaction, and Ventricular Septal Defect Associated with an MYH7 Mutation. J Thorac Cardiovasc Surg. 2014;148(5):e223-6. doi: 10.1016/j.jtcvs.2014.08.049. Hirono K Hata Y Ibuki K Yoshimura N Familial Ebstein's Anomaly, Left Ventricular Noncompaction, and Ventricular Septal Defect Associated with an MYH7 Mutation J Thorac Cardiovasc Surg 2014 148 5 e223 e226 10.1016/j.jtcvs.2014.08.049 62. Neagoe O, Ciobanu A, Diaconu R, Mirea O, Donoiu I, Militaru C. A Rare Case of Familial Restrictive Cardiomyopathy, with Mutations in MYH7 and ABCC9 Genes. Discoveries. 2019;7(3):e99. doi: 10.15190/d.2019.12. Neagoe O Ciobanu A Diaconu R Mirea O Donoiu I Militaru C A Rare Case of Familial Restrictive Cardiomyopathy, with Mutations in MYH7 and ABCC9 Genes Discoveries 2019 7 3 e99 10.15190/d.2019.12 63. Dorn GW 2nd, McNally EM. Two Strikes and You're Out: Gene-Gene Mutation Interactions in HCM. Circ Res. 2014;115(2):208-10. doi: 10.1161/CIRCRESAHA.114.304383. Dorn GW 2nd McNally EM Two Strikes and You're Out: Gene-Gene Mutation Interactions in HCM Circ Res 2014 115 2 208 210 10.1161/CIRCRESAHA.114.304383 64. Blankenburg R, Hackert K, Wurster S, Deenen R, Seidman JG, Seidman CE, et al. ß-Myosin Heavy Chain Variant Val606met Causes Very Mild Hypertrophic Cardiomyopathy in Mice, but Exacerbates HCM Phenotypes in Mice Carrying Other HCM Mutations. Circ Res. 2014;115(2):227-37. doi: 10.1161/CIRCRESAHA.115.303178. Blankenburg R Hackert K Wurster S Deenen R Seidman JG Seidman CE et al ß-Myosin Heavy Chain Variant Val606met Causes Very Mild Hypertrophic Cardiomyopathy in Mice, but Exacerbates HCM Phenotypes in Mice Carrying Other HCM Mutations Circ Res 2014 115 2 227 237 10.1161/CIRCRESAHA.115.303178

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 10.36660/abchf.20240054 Artigo de Revisão Explorando o MYH7 nas Cardiomiopatias: Fatores Genéticos e Desfechos Clínicos 0000-0001-8649-976X Pires Lucas Vieira Lacerda Concepção e desenho da pesquisa Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo 1 * 0009-0003-7829-4408 Correia Vinícius Machado Concepção e desenho da pesquisa Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo 1 2 * 0000-0003-0982-0307 Lipari Layara Fernanda Vicente Pereira Concepção e desenho da pesquisa Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo 1 0000-0002-2612-8040 Andrade Fernanda Almeida Concepção e desenho da pesquisa Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo 3 0000-0002-9323-8805 Fernandes Fábio Concepção e desenho da pesquisa Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo 1 0000-0002-1116-6554 Madrini Vagner Junior Concepção e desenho da pesquisa, Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo 1 4 Carvalho Mariana Lombardi Peres de Concepção e desenho da pesquisa Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo 1 Napolitano Giovanna Concepção e desenho da pesquisa Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo 1 Silva Elisangela Aparecida da 1 0000-0003-4407-2906 Vilalva Kelvin Henrique Concepção e desenho da pesquisa Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo 1 Val Vitória Pelegrino do Concepção e desenho da pesquisa Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo 1 0000-0001-5464-1792 Krieger José Eduardo Concepção e desenho da pesquisa Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo 1 Brasil Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP – Brasil Brasil Sírio-Libanês Ensino e Pesquisa, São Paulo, SP – Brasil Brasil Universidade Federal de São Paulo (UNIFESP), São Paulo, SP – Brasil Brasil Hospital Israelita Albert Einstein, São Paulo, SP – Brasil :Vinícius Machado Correia • Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo – Av. Dr. Enéas Carvalho de Aguiar, 44. CEP 05403-000, Cerqueira César, São Paulo, SP – Brasil E-mail: viniciusmachado7@gmail.com

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Lidia Moura

Os autores contribuíram igualmente para este trabalho

 Resumo

O gene MYH7, que codifica a cadeia pesada da beta-miosina, é um componente crítico na integridade estrutural e funcional das células musculares cardíacas e esqueléticas. Variantes no MYH7 estão entre as causas genéticas mais comuns de cardiomiopatias, particularmente cardiomiopatia hipertrófica (CMH) e cardiomiopatia dilatada (CMD), e também foram implicadas na cardiomiopatia restritiva (CMR) e com hipertrabeculação do ventrículo esquerdo (HTVE). Esta revisão explora os mecanismos moleculares pelos quais as variantes do MYH7 levam a esses fenótipos diversos, com foco nas correlações genótipo-fenótipo que fundamentam as manifestações clínicas de cada condição. As variantes do MYH7 são principalmente do tipo missense concentradas no domínio da cabeça da miosina, afetando a função contrátil da proteína. Essas variantes levam a um amplo espectro de anormalidades cardíacas, desde o espessamento das paredes miocárdicas até a dilatação das câmaras cardíacas. A revisão também aborda as implicações mais amplas das mutações do MYH7, incluindo seu papel nas miopatias esqueléticas e possíveis associações com o câncer. Compreender os mecanismos patogênicos das variantes do MYH7 não apenas aumenta a precisão do diagnóstico, mas também embasa o desenvolvimento de terapias-alvo. À medida que a integração de conhecimentos genéticos na prática clínica continua a evoluir, o gene MYH7 permanece um ponto crucial para o avanço na gestão e no tratamento das cardiomiopatias, oferecendo aos pacientes esperança de melhores desfechos clínicos por meio da medicina de precisão.

 MYH7 Cardiomiopatia Hipertrófica Cardiomiopatia Dilatada Cardiomiopatias Genéticas Genes Sarcoméricos

Explorando o MYH7 nas Cardiomiopatias: Fatores Genéticos e Desfechos Clínicos

Espectro de cardiomiopatias do gene MYH7. CMD: cardiomiopatia dilatada; CMH: cardiomiopatia hipertrófica; HTVE: hipertrabeculação do ventrículo esquerdo; ECAM: eventos cardiovasculares adversos maiores; CMR: cardiomiopatia restritiva.

Integração da genética e da cardiologia: o papel do MYH7 nas cardiomiopatias

Nos últimos anos, o advento do sequenciamento de última geração (NGS) revolucionou os testes genéticos, levando a uma integração mais estreita entre a genética e a cardiologia na prática médica. À medida que nossa compreensão do genoma humano e sua relação com a saúde cardiovascular se aprofunda, vão se identificando inúmeras associações genótipo-fenótipo, fornecendo insights essenciais para o diagnóstico e tratamento das doenças cardíacas genéticas (DCG). Entre os vários genes implicados nas DCG, o MYH7 se destaca como um dos mais frequentemente associados, especialmente em grandes coortes envolvendo cardiomiopatias.1-3 Junto aos genes MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3 e ACTC1, o gene MYH7 faz parte do grupo de genes sarcoméricos, que estão predominantemente associados à cardiomiopatia hipertrófica (CMH). Nesse grupo, o MYH7 e o MYBPC3 são os principais genes envolvidos.4 Além disso, o MYH7 contribui significativamente para a cardiomiopatia dilatada (CMD) e também foi identificado em casos de cardiomiopatia restritiva (CMR) e hipertrabeculação ventricular esquerda (HTVE).5-7 Esta revisão explora a convergência de abordagens clínicas e moleculares no tratamento de distúrbios relacionados ao MYH7. Ao examinar os mecanismos moleculares subjacentes a essas condições, buscamos aprimorar nossa compreensão do espectro da doença e sua aplicação à prática clínica.

 Estrutura e função do gene Gene MYH7: Estrutura, domínios e significado funcional na contração muscular

O gene MYH7 (OMIM:160760) codifica a cadeia pesada da beta-miosina, uma proteína expressa predominantemente em células musculares cardíacas e esqueléticas. Localizado no cromossomo 14q12, o gene abrange 22.883 pares de bases e compreende 41 éxons, sendo os dois primeiros não codificantes e os éxons 37 e 38, formando uma estrutura fundida única. A proteína completa é composta de 1.935 aminoácidos.8,9 A miosina é uma proteína motora baseada em actina com atividade ATPase essencial para a contração muscular nos músculos cardíacos e esqueléticos. Juntamente com os filamentos finos de actina, a miosina constitui a unidade contrátil fundamental nos músculos (Figura 1).10

– Estrutura do sarcômero, relaxado (a) e contraído (b), destacando a relação entre filamento fino (actina) e filamento grosso (miosina), compondo a principal estrutura contrátil das células musculares.

O MYH7 é estruturalmente dividido em três domínios principais: o domínio tipo SH3 N-terminal da miosina (aminoácidos 31-81); o domínio da cabeça da miosina, que contém a unidade motora (aminoácidos 85-778) e o domínio IQ (aminoácidos 781-810); e o domínio da cauda da miosina (aminoácidos 839-1935), que consiste em padrões repetidos de 28 aminoácidos formando uma estrutura em espiral alfa-helicoidal.10,11 O domínio da cabeça da miosina é particularmente significativo, pois contém as regiões de ligação à actina (aminoácidos 655-667 e 757-771) e é responsável pelo poder contrátil da proteína. O domínio da cauda da miosina garante a fixação adequada da miosina ao sarcômero. Dentro deste domínio, quatro aminoácidos específicos, conhecidos como resíduos de “salto” (Thr1188, Glu1385, Glu1582 e Gly1807), interrompem a sequência repetitiva. Esses saltos modificam a estrutura em espiral em seus arredores, sendo que o último salto desempenha um papel crucial na incorporação da miosina à estrutura do sarcômero.10 A Figura 2 destaca a estrutura do MYH7.

– Esquema do gene MYH7 destacando as principais subunidades estruturais e domínios funcionais.

Variantes patogênicas no MYH7: Implicações clínicas

Numerosas variantes genéticas que afetam o MYH7 foram documentadas na literatura médica, sendo associadas a vários fenótipos, incluindo DCG (principalmente cardiomiopatias e algumas doenças congênitas, como a anomalia de Ebstein) e miopatias esqueléticas. Os mecanismos que levam a esses fenótipos diversos ainda não são completamente compreendidos. A análise de variantes relatadas em bancos de dados públicos de variação genética (por exemplo, ClinVar, DECIPHER, GnomAD) sugere que variantes de perda de função podem não ser causadoras de doenças para esse gene. Em 2018, o painel de especialistas em cardiomiopatia hereditária da ClinGen adaptou os critérios de classificação de variantes ACMG/AMP especificamente voltados para variantes do MYH7 em cardiomiopatias. O painel rebaixou os critérios PVS1 (variante nula prevista em um gene em que a perda de função é um mecanismo de doença conhecido)para força moderada devido à ausência de evidências suficientes que vinculem tais variantes a DCG.12,13 O tipo predominante de variante causadora de doenças no MYH7 consiste em mutações missense, particularmente agrupadas nos aminoácidos 167-931, que se sobrepõem amplamente ao domínio da cabeça da miosina. Essa região exibe um agrupamento estatisticamente significativo de variantes patogênicas.13

 Correlação genótipo-fenótipo Correlação entre variantes do MYH7 e fenótipos de cardiomiopatia

O gene MYH7 codifica a cadeia pesada da beta-miosina, uma proteína expressa em células musculares cardíacas e esqueléticas. Variantes genéticas no MYH7 podem levar a uma ampla gama de fenótipos, abrangendo várias formas de cardiomiopatias e miopatias esqueléticas14 (Figura Central).

 Cardiomiopatia hipertrófica relacionada ao MYH7: Fatores genéticos e apresentação clínica

A CMH é uma doença cardíaca hereditária caracterizada pela hipertrofia da parede do ventrículo esquerdo, que pode se estender até o ventrículo direito. Isso ocorre na ausência de outras condições que podem causar sobrecarga de pressão, como hipertensão ou estenose aórtica, ou condições que levam ao espessamento da parede ventricular, como doença de Fabry ou amiloidose cardíaca.6 Nos Estados Unidos, a prevalência de CMH com fenótipo manifesto é de aproximadamente 1:500 indivíduos. Essa prevalência aumenta para 1:200 quando se incluem indivíduos com genótipo positivo e fenótipo negativo.4,15 O diagnóstico depende principalmente de técnicas de imagem, como ecocardiografia ou ressonância magnética cardíaca.6,16 A CMH é caracterizada por desordem miocárdica que leva à hipertrofia dos sarcômeros e aos sintomas, incluindo dispneia, dor no peito, palpitações e morte súbita.17,18 A doença geralmente segue um padrão de herança autossômica dominante, embora alguns casos resultem de mutações de novo.19 As variantes do MYH7 estão associadas a fenótipos graves, incluindo fibrilação atrial, arritmias ventriculares, doenças do sistema de condução e idade mais precoce no diagnóstico.15,17 Os testes genéticos, geralmente conduzidos por meio de painéis que incluem o MYH7 e outros genes sarcoméricos, têm um rendimento diagnóstico que varia de 30%, em casos esporádicos, a 60%, em casos familiares.5,16 Aproximadamente 181 variantes missense no MYH7 são classificadas como “provavelmente patogênicas” ou “patogênicas” para CMH no ClinVar.14 Além disso, evidências recentes vinculam variantes específicas a fenótipos esperados na CMH 15,17 (Figura 3).

– Impacto da presença da variante sarcomérica no fenótipo da CMH. CMH: cardiomiopatia hipertrófica; HF: história familiar; MS: morte súbita; VSVE: via de saída do ventrículo esquerdo; HAS: hipertensão arterial sistêmica.

Cardiomiopatia dilatada relacionada ao MYH7: Patogênese e expressão fenotípica

A CMD é caracterizada por dilatação do ventrículo esquerdo e disfunção sistólica, definida por uma fração de ejeção abaixo de 50%.6 Essa condição não pode ser atribuída apenas a doenças valvares cardíacas, hipertensão sistêmica ou doença arterial coronariana.6 Vários fatores, incluindo infecções virais, abuso de álcool e uso de esteroides anabolizantes, podem contribuir para a CMD, juntamente com variantes genéticas que podem agir de forma independente ou dentro de um contexto multifatorial.6 A CMD frequentemente representa o estágio final de várias cardiomiopatias.18

Etiologicamente, a CMD pode ser dividida em causas genéticas e não genéticas. Causas não genéticas incluem miocardite (por vírus, bactérias, fungos, parasitas); toxinas (por exemplo, álcool, cocaína, anfetaminas, esteroides anabolizantes, hemocromatose); distúrbios endócrinos (hipo/hipertireoidismo, síndrome de Cushing, feocromocitoma, acromegalia, diabetes mellitus); deficiências nutricionais (selênio, tiamina, zinco, cobre, carnitina); distúrbios eletrolíticos (hipocalcemia, hipofosfatemia); condições periparto; doenças autoimunes (miocardite de células gigantes, granulomatose eosinofílica com poliangeíte, lúpus eritematoso sistêmico, sarcoidose, artrite reumatoide, doença celíaca, doenças inflamatórias intestinais); e medicamentos (quimioterápicos, medicamentos psiquiátricos, antirretrovirais).6

Variantes genéticas patogênicas ou provavelmente patogênicas estão presentes em aproximadamente 20-40% dos casos de CMD familiar e 15-25% dos casos de CMD não selecionados.20 Os genes mais comumente associados incluem LMNA, MYH7, TNNT2, TTN, RBM20 e BAG3.21-25 A maioria das variantes genéticas relacionadas à CMD segue um padrão de herança autossômica dominante, embora modos de herança autossômica recessiva, ligada ao X e mitocondrial, também tenham sido relatados.26,27

O MYH7 é o terceiro gene frequentemente associado à CMD.22 A maioria das variantes nesse gene não é truncada e apresenta alta penetrância em casos familiares, com uma proporção significativa de pacientes pediátricos.28-30 Aproximadamente 59 variantes missense e três variantes de perda de função no MYH7 são classificadas como “provavelmente patogênicas” ou “patogênicas” para CMD no ClinVar.14 O mecanismo patogênico das variantes do MYH7 na CMD contrasta com o da CMH, envolvendo contratilidade sarcomérica reduzida devido à atividade prejudicada da ATPase e velocidade de deslizamento reduzida ao longo dos filamentos de actina.31,32 Isso leva à dilatação ventricular e à remodelamento cardíaco.31,32

 Cardiomiopatia restritiva relacionada ao MYH7: Fundamentos genéticos e características clínicas

A CMR é caracterizada por fisiologia ventricular restritiva com diâmetros sistólico e diastólico normais ou reduzidos, fração de ejeção ventricular esquerda preservada e espessura normal da parede ventricular.6 A dilatação biatrial é comumente observada, mesmo com ventrículos de tamanho normal.6 A CMR geralmente representa um estágio inicial de certas doenças e pode progredir para CMD.6

As causas da CMR são divididas em duas categorias principais:

Disfunção miocárdica intrínseca: Inclui cardiomiopatias genéticas (por exemplo, variantes sarcoméricas, filamina A, titina); doenças de armazenamento (por exemplo, doença de Fabry, doença de Danon, doenças de armazenamento de glicogênio, síndrome PRKAG2, hemocromatose); e medicamentos (por exemplo, hidroxicloroquina).6,33

Distúrbios da matriz extracelular: Inclui doenças infiltrativas (por exemplo, amiloidose, sarcoidose, hiperoxalúria) e doenças fibróticas (por exemplo, radiação, quimioterapia, esclerose sistêmica, cardiomiopatia diabética).6,33

É essencial diferenciar a CMR de doenças endocárdicas que apresentam fisiologia restritiva, como fibrose endomiocárdica, hipereosinofilia, síndrome carcinoide, neoplasias e condições induzidas por radiação.6,33

A CMR familiar é normalmente herdada de forma autossômica dominante.34 Os principais genes envolvidos incluem TNNI3, TNNT2, ACTC1 e MYH7.34 Em alguns casos, a CMR familiar pode estar associada a defeitos de condução resultantes de variantes no gene DES, frequentemente acompanhados de miopatia esquelética.34 Outros padrões de herança menos comuns incluem herança autossômica recessiva (por exemplo, variantes em HFE e PRKAG2) e herança ligada ao X (por exemplo, doença de Anderson-Fabry).34

Especificamente, as variantes da CMR relacionadas ao MYH7 são predominantemente autossômicas dominantes e de natureza missense.34 No banco de dados ClinVar, duas variantes missense são classificadas como “patogênicas” ou “provavelmente patogênicas” com alta confiança, corroboradas por múltiplas referências.14

 MYH7 e hipertrabeculação do ventrículo esquerdo (HTVE): Um fenótipo controverso

A HTVE, previamente conhecida com miocárdio não compactado, continua sendo um tópico controverso, com alguns especialistas classificando-a como uma cardiomiopatia genética e outros vendo a trabeculação excessiva como uma característica morfológica presente em vários processos patológicos, não constituindo, portanto, uma doença distinta.35 A principal característica da HTVE é a presença de trabéculas proeminentes no ventrículo esquerdo e recessos intertrabeculares profundos que são contínuos com a cavidade do VE e distintos das artérias coronárias epicárdicas.35

Variantes associadas à HTVE envolvem uma gama diversificada de proteínas, incluindo aquelas relacionadas ao sarcômero, citoesqueleto, mitocôndrias, desmossomos, armazenamento e canais iônicos, todas implicadas em diferentes doenças cardíacas.36 Aproximadamente um terço dos casos de HTVE envolvem uma variante patogênica, com a maioria seguindo um padrão de herança autossômica dominante.37 Os genes mais frequentemente relacionados incluem MYH7, MYBPC3, ACTC1, TTN, LMNA, RBM20, ACTN2 e PRDM16, embora esses genes não sejam exclusivos da HTVE.35,37 Ao contrário da CMH e da CMD, variantes truncadas no MYH7 são consideradas patogênicas na HTVE.38 No ClinVar, sete variantes missense e quatro variantes de perda de função no MYH7 são classificadas como “patogênicas” ou “provavelmente patogênicas”.14 Pacientes com HTVE e variantes de MYH7 geralmente apresentam menor risco de eventos cardiovasculares adversos quando comparados àqueles com variantes de outros genes.39

 Expansão do espectro do MYH7: Miopatias esqueléticas e outras associações fenotípicas

Pacientes com variantes MYH7 podem apresentar uma ampla gama de fenótipos clínicos, incluindo cardiomiopatia isolada, miopatia muscular esquelética isolada ou uma combinação de ambas.40 Embora esta revisão se concentre em cardiomiopatias, as doenças musculares esqueléticas relacionadas ao MYH7 são predominantemente autossômicas dominantes e podem se manifestar da infância à idade adulta, exibindo considerável variabilidade clínica e prognóstica.41 As principais miopatias esqueléticas associadas ao MYH7 incluem miopatia distal de Laing, miopatia de depósito de miosina, miopatia congênita com desproporção do tipo de fibra e distrofia muscular escapuloperoneal de início tardio relacionada ao MYH7.14

Além disso, o MYH7 parece desempenhar um papel na tumorigênese. Em pacientes com adenocarcinoma de pulmão associado ao tabagismo, 12% apresentam variantes MYH7, que estão associadas à progressão do câncer e ao pior prognóstico.42 O MYH7 também foi associado ao câncer de próstata, câncer oral e colangiocarcinoma intra-hepático associado ao vírus Epstein-Barr.43-45 Tanto variantes “patogênicas” ou “possivelmente patogênicas” quanto alterações na expressão genética podem influenciar o início e a progressão do câncer.41-45

 Fatores prognósticos e implicações clínicas das variantes do MYH7 nas cardiomiopatias

Além das diversas associações fenotípicas, vários estudos identificaram fatores prognósticos significativos relacionados às variantes do MYH7 (Figura 4). Um estudo de coorte multicêntrico holandês, envolvendo 581 indivíduos (30,1% pacientes índice, 48,4% homens, com mediana de idade de 37 anos) diagnosticados com CMH, HTVE ou CMD, descobriu que a penetrância precoce e eventos cardiovasculares maiores (ECAM) foram mais prevalentes em portadores de variantes MYH7 associadas a HTVE e CMD, em comparação com aqueles com CMH. Especificamente, ECAM ocorreram em 21,2% e 12,0% dos portadores de HTVE e CMD, respectivamente, versus 2,9% e 2,1% dos portadores de CMH.46 O risco de ECAM foi significativamente maior em indivíduos com histórico familiar de ECAM precoce (HR ajustado: 1,82; IC de 95%: 1,15-2,87; p = 0,010) ou aqueles com fenótipos de HTVE ou CMD diagnosticados em ≤5 anos de idade (HR ajustado: 38,82; IC de 95%: 5,16-291,88;p <0,001).46 Esses achados sugerem a necessidade de triagem precoce, especialmente para portadores de variantes associadas a HTVE ou CMD, bem como aqueles com histórico familiar de ECAM antes dos 12 anos.46

– Fatores prognósticos das cardiomiopatias do MYH7. ECAM: eventos cardiovasculares adversos maiores.

Outro estudo de coorte multicêntrico com mediana de acompanhamento de 4,5 anos examinou 147 pacientes com variantes do MYH7 associadas à CMD, dos quais 72,1% tinham CMD no início do estudo. 47 Durante o acompanhamento, 23,7% dos portadores inicialmente com fenótipo negativo desenvolveram CMD, e 28% exibiram remodelamento ventricular esquerdo reverso.47 A incidência de ECAM em 5 anos foi de 11,6%, incluindo cinco mortes por insuficiência cardíaca avançada e cinco transplantes cardíacos.47 A incidência de arritmias ventriculares foi baixa (1% em 5 anos, aumentando para 5% com FEVE ≤35%), o que é menor quando comparado à CMD associada a variantes do gene LMNA.47

O tipo de variante do MYH7 também influencia os resultados clínicos. Uma série de casos relatou que as variantes R453C e R453H do MYH7 estavam associadas a fenótipos graves de CMH que exigiam intervenções avançadas para insuficiência cardíaca. 48 Variantes missense no MYH7 relevantes para o desenvolvimento de CMH estão localizadas predominantemente nas regiões S1 e S2 do gene. 49 Estudos recentes confirmaram que variantes no domínio conversor e resíduos dentro da “mesa” de miosina são locais comuns para variantes MYH7 associadas à CMH, que tendem a aparecer mais cedo, progredir mais rapidamente e se sobrepor a outros fenótipos, em comparação com variantes em outras regiões do gene.50

Além disso, o efeito cumulativo de múltiplas variantes do MYH7 agrava a gravidade da CMH, levando a um início mais precoce, a um risco maior de morte súbita cardíaca (MSC) e a um prognóstico pior.51-63 Um modelo de camundongo demonstrou esse efeito aditivo: camundongos com uma única variante missense (p.Val606Met) exibiram um fenótipo relativamente benigno, enquanto camundongos com variantes patogênicas duplas (p.V606M e p.R453C ou p.V606M e p.R719W) desenvolveram um fenótipo hipertrófico mais pronunciado.64

 Conclusão

O MYH7 é um gene sarcomérico essencial para a fisiopatologia das cardiomiopatias, particularmente CMH e CMD, e contribui para fenótipos menos comuns, como CMR e HTVE. Além disso, certas variantes do MYH7 estão associadas a miopatias esqueléticas, às vezes se sobrepondo a cardiomiopatias. Avanços na compreensão das variantes genéticas do MYH7 e seus impactos funcionais aumentaram significativamente nosso conhecimento sobre os mecanismos moleculares subjacentes a essas condições.

Integrar o diagnóstico genético com a avaliação clínica é essencial para a gestão eficaz do paciente, permitindo uma abordagem personalizada que considera tanto os perfis genéticos quanto as manifestações clínicas individuais. Tecnologias emergentes, incluindo edição genética e terapias moleculares, prometem intervenções mais direcionadas e eficazes. O sucesso dessas abordagens depende da colaboração contínua entre cardiologistas, geneticistas e pesquisadores, enfatizando a importância da prática clínica alinhada com descobertas genéticas robustas.

Olhando para o futuro, a gestão de cardiomiopatias associadas ao MYH7 e condições genéticas relacionadas dependerá cada vez mais da interseção de pesquisa genética de ponta e aplicação clínica meticulosa. Essa integração visa melhorar os resultados e a qualidade de vida dos pacientes por meio de medicina personalizada e estratégias terapêuticas avançadas.

Não há vinculação deste estudo a programas de pós-graduação.

Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.

O presente estudo não teve fontes de financiamento externas.