The genetics of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere and associated proteins. Knowledge of the genetic pathophysiology of the disease has advanced significantly since the initial identification of a point mutation in the beta-myosin heavy chain (MYH7) gene in 1990. Other genetic causes of the disease include mutations in genes coding for proteins implicated in calcium handling or which form part of the cytoskeleton. The recent emergence of next-generation sequencing allows quicker and less expensive identification of causative mutations. However, a causative mutation is not identified in up to 50% of probands. At present, the primary clinical role of genetic testing in hypertrophic cardiomyopathy is in the context of familial screening, allowing the identification of those at risk of developing the condition. Genetic testing can also be used to exclude genocopies, particularly in the presence of certain diagnostic ‘red flag’ features, where lysosomal, glycogen storage, neuromuscular or Ras-MAPK pathway disorders may be suspected. The role of individual mutations in predicting prognosis is limited at present. However, the higher incidence of sudden cardiac death in the presence of a family history of such, suggests that genetics play a significant role in determining outcome. With an increased understanding of the impact of these mutations on a cellular level and on longer-term clinical outcomes, the aim in future for gene and mutation specific prognosis or potential disease-modifying therapy is closer.

Download Full-text

Hypertrophic cardiomyopathy: genetics

ESC CardioMed ◽

10.1093/med/9780198784906.003.0350_update_001 ◽

2018 ◽

pp. 1443-1450

Author(s):

Mohammed Majid Akhtar ◽

Luis Rocha Lopes

Keyword(s):

Genetic Testing ◽

Hypertrophic Cardiomyopathy ◽

Mapk Pathway ◽

Glycogen Storage ◽

Cellular Level ◽

Causative Mutation ◽

Clinical Role ◽

Genes Encoding ◽

Associated Proteins

Hypertrophic cardiomyopathy is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere and associated proteins. Knowledge of the genetic pathophysiology of the disease has advanced significantly since the initial identification of a point mutation in the beta-myosin heavy chain (MYH7) gene in 1990. Other genetic causes of the disease include mutations in genes coding for proteins implicated in calcium handling or which form part of the cytoskeleton. The recent emergence of next-generation sequencing allows quicker and less expensive identification of causative mutations. However, a causative mutation is not identified in up to 50% of probands. At present, the primary clinical role of genetic testing in hypertrophic cardiomyopathy is in the context of familial screening, allowing the identification of those at risk of developing the condition. Genetic testing can also be used to exclude genocopies, particularly in the presence of certain diagnostic ‘red flag’ features, where lysosomal, glycogen storage, neuromuscular or Ras-MAPK pathway disorders may be suspected. The role of individual mutations in predicting prognosis is limited at present. However, the higher incidence of sudden cardiac death in the presence of a family history of such, suggests that genetics play a significant role in determining outcome. With an increased understanding of the impact of these mutations on a cellular level and on longer-term clinical outcomes, the aim in future for gene and mutation specific prognosis or potential disease-modifying therapy is closer.

Download Full-text

Reconnoitering the Role of Long-Noncoding RNAs in Hypertrophic Cardiomyopathy: A Descriptive Review

International Journal of Molecular Sciences ◽

10.3390/ijms22179378 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9378

Author(s):

Syeda K. Shahzadi ◽

Nerissa Naidoo ◽

Alawi Alsheikh-Ali ◽

Manfredi Rizzo ◽

Ali A. Rizvi ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Direct Consequence ◽

Calcium Sensitivity ◽

Biological Processes ◽

Functional Roles ◽

Hereditary Cardiomyopathy ◽

Genes Encoding ◽

Non Coding Rnas ◽

Sarcomere Proteins

Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy. It is characterized by an unexplained non-dilated hypertrophy of the left ventricle with a conserved or elevated ejection fraction. It is a genetically heterogeneous disease largely caused by variants of genes encoding for cardiac sarcomere proteins, including MYH7, MYBPC3, ACTC1, TPM1, MYL2, MYL3, TNNI3, and TNNT23. Preclinical evidence indicates that the enhanced calcium sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric variations but may also result from secondary mutation-driven alterations. Long non-coding RNAs (lncRNAs) are a large class of transcripts ≥200 nucleotides in length that do not encode proteins. Compared to coding mRNAs, most lncRNAs are not as well-annotated and their functions are greatly unexplored. Nevertheless, increasing evidence shows that lncRNAs are involved in a variety of biological processes and diseases including HCM. Accumulating evidence has indicated that lncRNAs are dysregulated in HCM, and closely related to sarcomere construction, calcium channeling and homeostasis of mitochondria. In this review, we have summarized the known regulatory and functional roles of lncRNAs in HCM.

Download Full-text

Genetic and Epigenetic Aspects of Atopic Dermatitis

International Journal of Molecular Sciences ◽

10.3390/ijms21186484 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6484 ◽

Cited By ~ 1

Author(s):

Bogusław Nedoszytko ◽

Edyta Reszka ◽

Danuta Gutowska-Owsiak ◽

Magdalena Trzeciak ◽

Magdalena Lange ◽

...

Keyword(s):

Atopic Dermatitis ◽

Treatment Strategies ◽

Structural Proteins ◽

Epigenetic Changes ◽

Epigenetic Alterations ◽

Adaptive Immune ◽

Genes Encoding ◽

Inflammatory Processes ◽

Non Coding Rnas

Atopic dermatitis is a heterogeneous disease, in which the pathogenesis is associated with mutations in genes encoding epidermal structural proteins, barrier enzymes, and their inhibitors; the role of genes regulating innate and adaptive immune responses and environmental factors inducing the disease is also noted. Recent studies point to the key role of epigenetic changes in the development of the disease. Epigenetic modifications are mainly mediated by DNA methylation, histone acetylation, and the action of specific non-coding RNAs. It has been documented that the profile of epigenetic changes in patients with atopic dermatitis (AD) differs from that observed in healthy people. This applies to the genes affecting the regulation of immune response and inflammatory processes, e.g., both affecting Th1 bias and promoting Th2 responses and the genes of innate immunity, as well as those encoding the structural proteins of the epidermis. Understanding of the epigenetic alterations is therefore pivotal to both create new molecular classifications of atopic dermatitis and to enable the development of personalized treatment strategies.

Download Full-text

Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic cardiomyopathy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00913.2013 ◽

2014 ◽

Vol 306 (6) ◽

pp. H807-H815 ◽

Cited By ~ 29

Author(s):

David Barefield ◽

Mohit Kumar ◽

Pieter P. de Tombe ◽

Sakthivel Sadayappan

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Functional Impairments ◽

Tissue Samples ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Genes Encoding ◽

Heterozygous Carriers ◽

Sarcomere Proteins ◽

Whole Heart

The etiology of hypertrophic cardiomyopathy (HCM) has been ascribed to mutations in genes encoding sarcomere proteins. In particular, mutations in MYBPC3, a gene which encodes cardiac myosin binding protein-C (cMyBP-C), have been implicated in over one third of HCM cases. Of these mutations, 70% are predicted to result in C′-truncated protein products, which are undetectable in tissue samples. Heterozygous carriers of these truncation mutations exhibit varying penetrance of HCM, with symptoms often occurring later in life. We hypothesize that heterozygous carriers of MYBPC3 mutations, while seemingly asymptomatic, have subtle functional impairments that precede the development of overt HCM. This study compared heterozygous (+/t) knock-in MYBPC3 truncation mutation mice with wild-type (+/+) littermates to determine whether functional alterations occur at the whole-heart or single-cell level before the onset of hypertrophy. The +/t mice show ∼40% reduction in MYBPC3 transcription, but no changes in cMyBP-C level, phosphorylation status, or cardiac morphology. Nonetheless, +/t mice show significantly decreased maximal force development at sarcomere lengths of 1.9 μm (+/t 68.5 ± 4.1 mN/mm2 vs. +/+ 82.2 ± 3.2) and 2.3 μm (+/t 79.2 ± 3.1 mN/mm2 vs. +/+ 95.5 ± 2.4). In addition, heterozygous mice show significant reductions in vivo in the early/after (E/A) (+/t 1.74 ± 0.12 vs. +/+ 2.58 ± 0.43) and E′/A′ (+/t 1.18 ± 0.05 vs. +/+ 1.52 ± 0.15) ratios, indicating diastolic dysfunction. These results suggest that seemingly asymptomatic heterozygous MYBPC3 carriers do suffer impairments that may presage the onset of HCM.

Download Full-text

Epigenetic targeting and personalized approaches for AML

Hematology ◽

10.1182/asheducation-2014.1.44 ◽

2014 ◽

Vol 2014 (1) ◽

pp. 44-51 ◽

Cited By ~ 9

Author(s):

Gail J. Roboz

Keyword(s):

Molecular Genetic ◽

Treatment Strategies ◽

Regulation Of Transcription ◽

Hematopoietic Stem ◽

Genetic Characteristics ◽

Sequencing Technologies ◽

Recurrent Mutations ◽

Genes Encoding ◽

Cell Disorder

Abstract Acute myeloid leukemia (AML) is a genetically heterogeneous clonal hematopoietic stem cell disorder and the majority of patients with AML die from their disease. The treatment paradigms for AML were developed decades ago and, although there have been improvements in the outcomes of selected younger patients and those with specific cytogenetic and molecular genetic characteristics, the overall survival for older patients remains dismal. Over the last few years, next-generation sequencing technologies have identified recurrent mutations in genes encoding proteins involved in the epigenetic regulation of transcription in most patients with AML. This discovery has led to new insights into the role of the epigenome in AML and opens the possibility of epigenetically targeted therapies. This chapter describes how epigenetic dysregulation plays a role in AML and highlights current and future treatment strategies that attempt to exploit epigenetic targets.

Download Full-text

Protein Quality Control Activation and Microtubule Remodeling in Hypertrophic Cardiomyopathy

Cells ◽

10.3390/cells8070741 ◽

2019 ◽

Vol 8 (7) ◽

pp. 741 ◽

Cited By ~ 2

Author(s):

Dorsch ◽

Schuldt ◽

Remedios ◽

Schinkel ◽

Jong ◽

...

Keyword(s):

Quality Control ◽

Hypertrophic Cardiomyopathy ◽

Protein Quality ◽

Protein Quality Control ◽

Left Ventricular ◽

Microtubule Network ◽

Protein Levels ◽

Tubulin Acetylation ◽

Genes Encoding ◽

Sarcomere Proteins

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder. It is mainly caused by mutations in genes encoding sarcomere proteins. Mutant forms of these highly abundant proteins likely stress the protein quality control (PQC) system of cardiomyocytes. The PQC system, together with a functional microtubule network, maintains proteostasis. We compared left ventricular (LV) tissue of nine donors (controls) with 38 sarcomere mutation-positive (HCMSMP) and 14 sarcomere mutation-negative (HCMSMN) patients to define HCM and mutation-specific changes in PQC. Mutations in HCMSMP result in poison polypeptides or reduced protein levels (haploinsufficiency, HI). The main findings were 1) several key PQC players were more abundant in HCM compared to controls, 2) after correction for sex and age, stabilizing heat shock protein (HSP)B1, and refolding, HSPD1 and HSPA2 were increased in HCMSMP compared to controls, 3) α-tubulin and acetylated α-tubulin levels were higher in HCM compared to controls, especially in HCMHI, 4) myosin-binding protein-C (cMyBP-C) levels were inversely correlated with α-tubulin, and 5) α-tubulin levels correlated with acetylated α-tubulin and HSPs. Overall, carrying a mutation affects PQC and α-tubulin acetylation. The haploinsufficiency of cMyBP-C may trigger HSPs and α-tubulin acetylation. Our study indicates that proliferation of the microtubular network may represent a novel pathomechanism in cMyBP-C haploinsufficiency-mediated HCM.

Download Full-text

The role of genetic testing in cardiac deaths under suspicion of hypertrophic cardiomyopathy: validating a low-cost method and presenting preliminary data of an Italian retrospective study

Romanian Journal of Legal Medicine ◽

10.4323/rjlm.2017.297 ◽

2017 ◽

Vol 25 (3) ◽

pp. 297-300

Author(s):

Camilla Tettamanti ◽

Alessandro Bonsignore ◽

Simonetta Verdiani ◽

Lucia Casarino ◽

Francesco De Stefano ◽

...

Keyword(s):

Retrospective Study ◽

Genetic Testing ◽

Hypertrophic Cardiomyopathy ◽

Preliminary Data ◽

Low Cost

Download Full-text

Unraveling the Genotype‐Phenotype Relationship in Hypertrophic Cardiomyopathy: Obesity‐Related Cardiac Defects as a Major Disease Modifier

Journal of the American Heart Association ◽

10.1161/jaha.120.018641 ◽

2020 ◽

Vol 9 (22) ◽

Author(s):

Edgar E. Nollet ◽

B. Daan Westenbrink ◽

Rudolf A. de Boer ◽

Diederik W. D. Kuster ◽

Jolanda van der Velden

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Disease Burden ◽

Clinical Course ◽

Clinical Findings ◽

Inherited Cardiomyopathy ◽

Genes Encoding ◽

Disease Penetrance ◽

Disease Modifier ◽

Sarcomere Proteins ◽

Recent Cohort

Abstract Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric septal thickening and diastolic dysfunction. More than 1500 mutations in genes encoding sarcomere proteins are associated with HCM. However, the genotype‐phenotype relationship in HCM is incompletely understood and involves modification by additional disease hits. Recent cohort studies identify obesity as a major adverse modifier of disease penetrance, severity, and clinical course. In this review, we provide an overview of these clinical findings. Moreover, we explore putative mechanisms underlying obesity‐induced sensitization and aggravation of the HCM phenotype. We hypothesize obesity‐related stressors to impact on cardiomyocyte structure, metabolism, and homeostasis. These may impair cardiac function by directly acting on the primary mutation‐induced myofilament defects and by independently adding to the total cardiac disease burden. Last, we address important clinical and pharmacological implications of the involvement of obesity in HCM disease modification.

Download Full-text