Familial Hypertrophic Cardiomyopathy: Diagnosis and Management

Litt, M.; Ali, Ayan; Reza, Nosheen

doi:10.2147/vhrm.s365001

Cited by 11 publications

(14 citation statements)

References 81 publications

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“…Most of the HCM positive-genetic test cases are caused by pathogenic variants (PV) in the sarcomeric genes, referred to as sarcomere-positive HCM ( Table 1 ) [ 2 ]. Myosin heavy chain 7 ( MYH7 ) and myosin-binding protein C3 ( MYBPC3 ), encoding β-myosin heavy chain and myosin-binding protein C, respectively, are the two most common causal genes and are responsible for approximately 40% of all HCM cases and up to 70% of familial cases [ 11 ].…”

Section: Genetic Basis Of Hcmmentioning

confidence: 99%

“…Hypertrophic cardiomyopathy (HCM) is a disease with a high burden of morbidity and mortality and is the most frequent cause of sudden cardiac death (SCD) in young athletes [ 1 ]. It is the most common inherited cardiomyopathy and one of the most prevalent genetic cardiovascular diseases [ 2 , 3 ]. Its prevalence ranges from 1:200 to 1:500 adults, currently affecting more than 750,000 individuals in the United States [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…It is the most common inherited cardiomyopathy and one of the most prevalent genetic cardiovascular diseases [ 2 , 3 ]. Its prevalence ranges from 1:200 to 1:500 adults, currently affecting more than 750,000 individuals in the United States [ 2 ]. HCM may be characterized by dynamic left ventricular (LV) outflow obstruction, diastolic dysfunction, myocardial ischemia, and myocardial fibrosis and remodeling that increase susceptibility to severe arrhythmias [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…HCM is classified depending on the presence of positive family history or positive genetic test into familial (60%) and non-familial HCM (40%) [ 7 , 8 , 9 ]. Most of the familial cases follow autosomal dominant inheritance with incomplete penetrance, variable expressivity, and heterogeneity [ 2 , 6 ]. The remainder of the familial cases include different patterns of inheritance or HCM in the context of syndromes or other genetic disorders, particularly in children [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Role of Genetics in Diagnosis and Management of Hypertrophic Cardiomyopathy: A Glimpse into the Future

Abbas,

Baba Ali,

Farina

et al. 2024

Biomedicines

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Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. It follows an autosomal dominant inheritance pattern in most cases, with incomplete penetrance and heterogeneity. It is familial in 60% of cases and most of these are caused by pathogenic variants in the core sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1). Genetic testing using targeted disease-specific panels that utilize next-generation sequencing (NGS) and include sarcomeric genes with the strongest evidence of association and syndrome-associated genes is highly recommended for every HCM patient to confirm the diagnosis, identify the molecular etiology, and guide screening and management. The yield of genetic testing for a disease-causing variant is 30% in sporadic cases and up to 60% in familial cases and in younger patients with typical asymmetrical septal hypertrophy. Genetic testing remains challenging in the interpretation of results and classification of variants. Therefore, in 2015 the American College of Medical Genetics and Genomics (ACMG) established guidelines to classify and interpret the variants with an emphasis on the necessity of periodic reassessment of variant classification as genetic knowledge rapidly expands. The current guidelines recommend focused cascade genetic testing regardless of age in phenotype-negative first-degree relatives if a variant with decisive evidence of pathogenicity has been identified in the proband. Genetic test results in family members guide longitudinal clinical surveillance. At present, there is emerging evidence for genetic test application in risk stratification and management but its implementation into clinical practice needs further study. Promising fields such as gene therapy and implementation of artificial intelligence in the diagnosis of HCM are emerging and paving the way for more effective screening and management, but many challenges and obstacles need to be overcome before establishing the practical implications of these new methods.

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Section: Genetic Basis Of Hcmmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Role of Genetics in Diagnosis and Management of Hypertrophic Cardiomyopathy: A Glimpse into the Future

Abbas,

Baba Ali,

Farina

et al. 2024

Biomedicines

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“…The prevalence of HCM is 1:500 in the general population [2]. Striking cardiomegaly and stunning asymmetry with disproportionate involvement of interventricular septum was observed in many HCM cases [3]. Postmortem examination in hearts of HCM victims show myocyte disarray accompanied with significantly increased myocardial fibrosis [4].…”

Section: Introductionmentioning

confidence: 99%

A Novel Truncating Variant in MYBPC3 Causes Hypertrophic Cardiomyopathy

Zhang,

Gong,

Cong

et al. 2024

Preprint

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BackgroundFamilial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease. Related mutations contributing to hypercontractility and poor relaxation in HCM have been incompletely understood. The purpose of this study was to explore and verify a novel variant in cardiac myosin-binding protein C3 (MYBPC3) in a HCM family.MethodsClinical information was collected and cardiac evaluation was performed in the pedigree. Second-generation sequencing technology was used to investigate the proband and his family. Computational prediction of mutation effects at genomic level and 3D visualization of the mutated protein were achieved by in silico analysis.ResultsTypical interventricular septal thickening was detected in all the four HCM patients. A c.1042_1043insCGGCA mutation of MYBPC3 was verified in the proband and family members. Mild phenotype associated with delayed onset and relative favorable prognosis were observed in the pedigree. In silico analysis of the mutation revealed that c.1042_1043insCGGCA led to an early termination of MYBPC protein synthesis at C2 domain, losing the domains that are essential for myosin-and titin-binding.ConclusionThe novel c.1042_1043insCGGCA mutation of MYBPC3 was a genetic basis for HCM.Our gene sequence based computational analysis predicted the pathogenicity of the mutation by correlating MYBPC3 genotypes with clinical phenotypes.

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Pharmacokinetics, disposition, and biotransformation of the cardiac myosin inhibitor aficamten in humans

Xu,

Divanji,

Griffith

et al. 2024

Pharmacology Res & Perspec

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Aficamten, a cardiac myosin inhibitor, is being developed for the treatment of patients with symptomatic hypertrophic cardiomyopathy (HCM). The purpose of this study was to determine the absorption, metabolism, and excretion of aficamten. Eight healthy male participants received a single oral dose of 20 mg aficamten (containing approximately 100 μCi of radiocarbon). Blood, urine, and feces samples were collected up to a maximum of Day 26. The pharmacokinetics of aficamten were characterized by moderate absorption, with a median tmax of 2.0 h postdose. The median t1/2 of aficamten was 99.6 h with similar t1/2 observed for metabolites and total radioactivity in plasma and whole blood. The overall total recovery of administered total radioactivity was 89.7% with 57.7% of the dose recovered in feces and 32.0% in urine. The main circulating metabolites in plasma included monohydroxylated metabolites M1a (CK‐3834282) and M1b (CK‐3834283) accounting for 10.5% and 36.4% of the total radioactivity AUC both with a median tmax of 5 h. The other major plasma metabolite was M5 (an oxygen‐linked glucuronide conjugate of M1a), which accounted for 10.3% of the total plasma radioactivity exposure, with a tmax of 24 h. In urine, M5 was the most abundant metabolite with 8.02% total radioactive dose (TRD), followed by M1a and M1b with 6.16% and 2.85% TRD, respectively; however, there were no metabolites in urine observed at >10% of dose. The major metabolite in feces was M18 representing 44.1% of the radioactive dose. These findings indicated that aficamten was eliminated by metabolism, and to a minor extent, by fecal excretion of unchanged aficamten with renal excretion playing a minor role. Feces were the principal route of excretion of the radioactive dose.

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Familial Hypertrophic Cardiomyopathy: Diagnosis and Management

Cited by 11 publications

References 81 publications

Role of Genetics in Diagnosis and Management of Hypertrophic Cardiomyopathy: A Glimpse into the Future

Role of Genetics in Diagnosis and Management of Hypertrophic Cardiomyopathy: A Glimpse into the Future

A Novel Truncating Variant in MYBPC3 Causes Hypertrophic Cardiomyopathy

Pharmacokinetics, disposition, and biotransformation of the cardiac myosin inhibitor aficamten in humans

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