• Antiarrhythmic drugs
• Anticoagulants
• Drug–drug interaction
• Hypertrophic cardiomyopathy
• Mavacamten
• Pharmacogenomics
• Pharmacokinetics

• Humans
• Anti-Arrhythmia Agents/pharmacokinetics
• Anti-Arrhythmia Agents/administration & dosage
• Drug Interactions
• Anticoagulants/pharmacokinetics
• Anticoagulants/administration & dosage
• Benzylamines/pharmacokinetics
• Atrial Fibrillation/drug therapy
• Atrial Fibrillation/etiology
• Uracil/analogs & derivatives
• Uracil/pharmacokinetics
• Thiazepines/pharmacokinetics
• Cardiomyopathy, Hypertrophic/drug therapy
• Cardiomyopathy, Hypertrophic/complications
• Drug Therapy, Combination

• children
• dilated cardiomyopathy
• genetics
• genotype-phenotype correlation
• inherited cardiomyopathy

• cardiovascular disease
• end-stage
• genetic analysis
• hypertrophic cardiomyopathy
• sarcomere

• Humans
• Cardiomyopathy, Hypertrophic/genetics
• Male
• Female
• Middle Aged
• Sarcomeres/genetics
• Disease Progression
• Adult
• Aged
• Japan/epidemiology
• Genetic Variation
• Heart Failure/genetics

• cardiac therapeutics
• cardiomyopathies
• hypertrophic cardiomyopathy
• mavacamten

• coinheritance
• distinct cardiomyopathies
• pathogenic variants

• Calcium sensitivity
• Cardiac myosin binding protein C
• Contractility
• Genotype-phenotype correlation
• Hypertrophic cardiomyopathy
• Murine models
• cMyBP-C W792R

• Animals
• Mutation, Missense
• Cardiomyopathy, Hypertrophic/genetics
• Cardiomyopathy, Hypertrophic/metabolism
• Cardiomyopathy, Hypertrophic/physiopathology
• Cardiomyopathy, Hypertrophic/pathology
• Myocardial Contraction/genetics
• Mice
• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• Animals, Newborn
• Myocardium/metabolism
• Protein Domains
• Sarcomeres/metabolism
• Calcium/metabolism
• Disease Models, Animal
• Gene Knock-In Techniques

• MYBPC3
• cardiogenetic
• founder variant
• hypertrophic cardiomyopathy
• phenotyping

• TTN
• Cardiomyopathy
• Genetic
• Titin
• Variant

• Humans
• Connectin/genetics
• Cardiomyopathies/genetics
• Early Intervention, Educational
• Genetic Counseling
• Genetic Testing

• age of onset
• cardiomyopathy, hypertrophic
• penetrance

• Humans
• Adult
• Penetrance
• Mutation
• Cross-Sectional Studies
• Pedigree
• Cardiomyopathy, Hypertrophic/diagnosis
• Cardiomyopathy, Hypertrophic/epidemiology
• Cardiomyopathy, Hypertrophic/genetics
• Troponin T/genetics

• R01 HL155568 NHLBI NIH HHS
• P50 HL112349 NHLBI NIH HHS
• U01 HL117006 NHLBI NIH HHS

• Hypertrophic cardiomyopathy
• homozygous
• left ventricular hypertrophy

• Humans
• Child, Preschool
• Cardiomyopathy, Hypertrophic/complications
• Cardiomyopathy, Hypertrophic/diagnosis
• Cardiomyopathy, Hypertrophic/genetics
• Mutation
• Death, Sudden, Cardiac/etiology
• Disease Progression
• Prognosis

• Gene variants
• Hypertrophic cardiomyopathy
• MYBPC3
• MYH7
• Sudden death

• Male
• Humans
• Cardiomyopathy, Hypertrophic/genetics
• Heart Diseases
• High-Throughput Nucleotide Sequencing
• Death, Sudden
• Mutation
• Solute Carrier Family 22 Member 5/genetics

• Instituto Mexicano del Seguro Social

• DCM
• HCM
• MYBPC3
• cardiomyopathy
• sarcomere genes

• Rani DS has been supported by the CSIR-CCMB, Hyderabad, Telangana, India. K Thangaraj has been supported by the JC Bose Fellowship
• SERB, DST, and The Government of India. However, the funders had no role in designing the study, the collection of data, the analysis of sequence data, the decision to publish, or the preparation of the manuscript

• Cardiomyopathy
• genetic testing
• precision medicine

• genetic testing
• hypertrophic cardiomyopathy (HCM)
• next generation sequencing

• cardiomyopathies
• pediatrics

• Adolescent
• Cardiac Myosins/genetics
• Cardiomyopathy, Hypertrophic/diagnosis
• Cardiomyopathy, Hypertrophic/genetics
• Carrier Proteins/genetics
• Child
• Child, Preschool
• Cytoskeletal Proteins/genetics
• Female
• Heart
• Humans
• Infant
• Male
• Mutation

• FS/16/72/32270 British Heart Foundation
• MR/T005181/1 Medical Research Council
• MR/T024062/1 Medical Research Council

• HPO terms
• MYBPC3
• MYH7
• cardiac phenotype
• region of homozygosity

• MYBPC3 gene
• familial hypertrophic cardiomyopathy
• heterozygous
• loss-of-function.
• novel variant

This study summarises the diagnostic validity and clinical utility of genetic testing for patients with hypertrophic cardiomyopathy (HCM) and their at-risk relatives.

A systematic search was performed in PubMed (MEDLINE), Embase, CINAHL and Cochrane Central Library databases from inception through 2 March 2020. Subgroup and sensitivity analyses were prespecified for individual sarcomere genes, presence/absence of pathogenic variants, paediatric and adult cohorts, family history, inclusion of probands, and variant classification method. Study quality was assessed using the Newcastle-Ottawa tool.

A total of 132 articles met inclusion criteria. The detection rate based on pathogenic and likely pathogenic variants was significantly higher in paediatric cohorts compared with adults (56% vs 42%; p=0.01) and in adults with a family history compared with sporadic cases (59% vs 33%; p=0.005). When studies applied current, improved, variant interpretation standards, the adult detection rate significantly decreased from 42% to 33% (p=0.0001) because less variants met criteria to be considered pathogenic. The mean difference in age-of-onset in adults was significantly earlier for genotype-positive versus genotype-negative cohorts (8.3 years; p<0.0001), MYH7 versus MYBPC3 cohorts (8.2 years; p<0.0001) and individuals with multiple versus single variants (7.0 years; p<0.0002). Overall, disease penetrance in adult cohorts was 62%, but differed significantly depending on if probands were included or excluded (73% vs 55%; p=0.003).

This systematic review and meta-analysis is the first, to our knowledge, to collectively quantify historical understandings of detection rate, genotype-phenotype associations and disease penetrance for HCM, while providing the answers to important routine clinical questions and highlighting key areas for future study.

• cardiomyopathy, hypertrophic
• genetic diseases, inborn
• systematic reviews as topic

• Cardiac Myosins/genetics
• Cardiomyopathy, Hypertrophic/genetics
• Cardiomyopathy, Hypertrophic, Familial/genetics
• Humans
• Mutation
• Myosin Heavy Chains/genetics
• Pedigree
• Phenotype

• RNA splicing
• cardiac myosin-binding protein C
• hypertrophic cardiomyopathy
• myosin
• nontruncating MYBPC3 variants
• protein nanomechanics
• protein stability
• sarcomere contraction
• truncating MYBPC3 variants
• variants of uncertain significance

Objective: Cardiac hypertrophy with varying degrees of myocardial fibrosis is commonly associated with coronary artery disease (CAD) related sudden cardiac death (SCD), especially in young victims among whom patterns of coronary artery lesions do not entirely appear to explain the cause of SCD. Our aim was to study the genetic background of hypertrophy, with or without fibrosis, among ischemic SCD victims with single vessel CAD.

Methods: The study population was derived from the Fingesture study, consisting of all autopsy-verified SCDs in Northern Finland between the years 1998 and 2017 (n = 5,869). We carried out targeted next-generation sequencing using a panel of 174 genes associated with myocardial structure and ion channel function in 95 ischemic-SCD victims (mean age 63.6 ± 10.3 years; 88.4% males) with single-vessel CAD in the absence of previously diagnosed CAD and cardiac hypertrophy with or without myocardial fibrosis at autopsy.

Results: A total of 42 rare variants were detected in 43 subjects (45.3% of the study subjects). Five variants in eight subjects (8.4%) were classified as pathogenic or likely pathogenic. We observed 37 variants of uncertain significance in 39 subjects (40.6%). Variants were detected in myocardial structure protein coding genes, associated with arrhythmogenic right ventricular, dilated, hypertrophic and left ventricular non-compaction cardiomyopathies. Also, variants were detected in ryanodine receptor 2 (RYR2), a gene associated with both cardiomyopathies and catecholaminergic polymorphic ventricular tachycardias.

Conclusions: Rare variants associated with cardiomyopathies, in the absence of anatomic evidence of the specific inherited cardiomyopathies, were common findings among CAD-related SCD victims with single vessel disease and myocardial hypertrophy found at autopsies, suggesting that these variants may modulate the risk for fatal arrhythmias and SCD in ischemic disease.

Hypertrophic cardiomyopathy (HCM) is associated with adverse left ventricular (LV) remodeling causing dysfunction and malignant arrhythmias. Severely affected patients present with disease onset during childhood and sudden cardiac death risk (SCD) stratification is of the highest importance in this cohort. This study aimed to investigate genotype–phenotype association regarding clinical outcome and disease progression in pediatric onset HCM. Medical charts from forty-nine patients with pediatric HCM who had undergone genetic testing were reviewed for retrospective analysis. Demographic, clinical, transthoracic echocardiographic, electrocardiographic, long-term electrocardiogram, cardiopulmonary exercise test, cardiac magnetic resonance, and medication data were recorded. Childhood onset HCM was diagnosed in 29 males and 20 females. Median age at last follow-up was 18.7 years (range 2.6–51.7 years) with a median follow-up time since diagnosis of 8.5 years (range 0.2–38.0 years). Comparison of patients carrying mutations in distinct genes and comparison of genotype-negative with genotype-positive individuals, revealed no differences in functional classification, LV morphology, hypertrophy, systolic and diastolic function, fibrosis and cardiac medication. Patients with compound mutations had a significantly higher risk for major arrhythmic events than a single-mutation carrier. No association between affected genes and disease severity or progression was identified in this cohort.

• genotype–phenotype association
• major arrhythmic events
• pediatric onset hypertrophic cardiomyopathy
• sudden cardiac death risk stratification

Hypertrophic cardiomyopathy (HCM), described as the presence of hypertrophy of left ventricular, is the most prevalent heritable cardiovascular disease with predominantly an autosomal dominant type of inheritance. However, pathogenic alleles are not identified in at least 25% of patients with HCM, and the spectrum of pathogenic variants that contribute to the development of HCM in Russia has not been fully described. Therefore, the goal of our study was to identify genetic variants associated with the etiopathogenesis of HCM in Russian patients.

The study cohort included 98 unrelated adult patients with HCM. We performed targeted exome sequencing, an analysis using various algorithms for prediction of the impact of variants on protein structure and the prediction of pathogenicity using ACMG Guidelines.

The frequency of pathogenic and likely pathogenic variants in all HCM‐related genes was 8% in our patients. We also identified 20 variants of uncertain significance in all HCM‐related genes.

The prevalence of individual pathogenic variants in HCM‐related genes in Russian population appears to be lower than in general European population, which could be explained by ethnic features of Russian population, age characteristics of our sample, or unidentified pathogenic variants in genes previously not linked with HCM.

• exome
• genetics
• hypertrophic cardiomyopathy
• next generation sequencing
• pathogenic variants

• Hypertrophic cardiomyopathy (HCM)
• Induced pluripotent stem cells (iPSC)
• Overload

• T34 GM083914 NIGMS NIH HHS
• T34 GM141639 NIGMS NIH HHS
• American Heart Association
• National Institute of General Medical Sciences

• Dilated cardiomyopathy
• Genetic mutations
• Next-generation sequencing
• Phenotype
• Vietnamese

• Adaptor Proteins, Signal Transducing/genetics
• Apoptosis Regulatory Proteins/genetics
• Cardiomyopathy, Dilated
• Cohort Studies
• Genetic Association Studies
• Genotype
• Humans
• Vietnam

• Cardiac MRI
• Fibrosis
• Genetics
• Hypertrophic cardiomyopathy

• arrhythmogenic right ventricular cardiomyopathy
• dilated cardiomyopathy
• hypertrophic cardiomyopathy
• precision medicine

• Cardiomyopathies/genetics
• Cardiomyopathies/therapy
• Humans
• Precision Medicine

• R01 HL130423 NHLBI NIH HHS
• R01 HL135093 NHLBI NIH HHS
• R01 HL148167 NHLBI NIH HHS

Variants in MYBPC3 causing loss of function are the most common cause of hypertrophic cardiomyopathy (HCM). However, a substantial number of patients carry missense variants of uncertain significance (VUS) in MYBPC3. We hypothesize that a structural-based algorithm, STRUM, which estimates the effect of missense variants on protein folding, will identify a subgroup of HCM patients with a MYBPC3 VUS associated with increased clinical risk.

Among 7,963 patients in the multicenter Sarcomeric Human Cardiomyopathy Registry (SHaRe), 120 unique missense VUS in MYBPC3 were identified. Variants were evaluated for their effect on subdomain folding and a stratified time-to-event analysis for an overall composite endpoint (first occurrence of ventricular arrhythmia, heart failure, all-cause mortality, atrial fibrillation, and stroke) was performed for patients with HCM and a MYBPC3 missense VUS.

We demonstrated that patients carrying a MYBPC3 VUS predicted to cause subdomain misfolding (STRUM+, ΔΔG ≤ −1.2 kcal/mol) exhibited a higher rate of adverse events compared with those with a STRUM- VUS (hazard ratio = 2.29, P = 0.0282). In silico saturation mutagenesis of MYBPC3 identified 4,943/23,427 (21%) missense variants that were predicted to cause subdomain misfolding.

STRUM identifies patients with HCM and a MYBPC3 VUS who may be at higher clinical risk and provides supportive evidence for pathogenicity.

• Ca(2+)-sensitivity
• Cardiomyopathy
• Human tissue
• Hypertrophic cardiomyopathy
• Mutant protein dose
• Mutation
• Mutation location
• Myofilament
• Protein level
• TNNT2
• Troponin
• Troponin T
• Troponin exchange

• Adolescent
• Adult
• Aged
• Calcium/metabolism
• Cardiomyopathy, Hypertrophic/genetics
• Cardiomyopathy, Hypertrophic/pathology
• Female
• Humans
• Male
• Middle Aged
• Mutant Proteins/metabolism
• Mutation/genetics
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/pathology
• Myofibrils/metabolism
• Myofibrils/pathology
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Troponin T/genetics

• R01 HL128683 NHLBI NIH HHS

• hypertrophic cardiomyopathy
• next-generation sequencing
• rare genetic variants

Hypertrophic cardiomyopathy has the highest incidence rate among genetically inherited cardiac diseases. It develops as a result of mutations in genes in related to the sarcomere protein in cardiac muscle. Generally, this results in asymmetrical hypertrophy. Patients who are symptomatic and have a significantly narrow left ventricular undergo should receive surgical treatment, whereas patients with a sudden cardiac death risk should receive treatment with an implantable cardiac defibrillator. This paper presents an infant with hypertrophic cardiomyopathy who was recently identified as having a mutation that resulted in a deletion-insertion type framework shift in the gene MYBPC3, who had family history of sudden death at a young age, and received myectomy and treatment with an implantable cardiac defibrillator in the same session due to a severely narrowed left ventricular outflow tract.

• Hypertrophic cardiomyopathy
• MYBPC3 gene
• implantable cardiac defibrillator
• new mutation
• septal myectomy

• Gene replacement
• Gene therapy
• Hypertrophic cardiomyopathy
• MYBPC3

Supplemental Digital Content is available in the text.

Pathogenic variants in MYBPC3, encoding cardiac MyBP-C (myosin binding protein C), are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped hypertrophic cardiomyopathy cohorts have precluded detailed genotype-phenotype correlations.

• actins
• genotype
• hypertrophic cardiomyopathy
• myosin
• sarcomere

• Heart failure
• Hypertrophic cardiomyopathy
• MYBPC3
• South Asian

• HL130356 NHLBI NIH HHS
• R01 HL105826 NHLBI NIH HHS
• R01 AR067279 NIAMS NIH HHS
• HL139680 NHLBI NIH HHS
• R56 HL139680 NHLBI NIH HHS
• AR067279 NIAMS NIH HHS
• American Heart Association (US)
• American Heart Association
• National Heart, Lung, and Blood Institute
• National Heart, Lung, and Blood Institute (US)
• National Institute of Arthritis and Musculoskeletal and Skin Diseases
• American Historical Association

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disease, is caused by several mostly heterozygous mutations in sarcomeric genes. Hallmarks of HCM are cardiomyocyte and myofibrillar disarray and hypertrophy and fibrosis of the septum and the left ventricle. To date, a pathomechanism common to all mutations remains elusive. We have proposed that contractile imbalance, an unequal force generation of neighboring cardiomyocytes, may contribute to development of HCM hallmarks. At the same calcium concentration, we found substantial differences in force generation between individual cardiomyocytes from HCM patients with mutations in β-MyHC (β-myosin heavy chain). Variability among cardiomyocytes was significantly larger in HCM patients as compared with donor controls. We assume that this heterogeneity in force generation among cardiomyocytes may lead to myocardial disarray and trigger hypertrophy and fibrosis. We provided evidence that burst-like transcription of the MYH7-gene, encoding for β-MyHC, is associated with unequal fractions of mutant per wild-type mRNA from cell to cell (cell-to-cell allelic imbalance). This will presumably lead to unequal fractions of mutant per wild-type protein from cell to cell which may underlie contractile imbalance. In this review, we discuss molecular mechanisms of burst-like transcription with regard to contractile imbalance and disease development in HCM.

• Burst-like transcription
• Cell-to-cell allelic imbalance
• Contractile imbalance
• Hypertrophic cardiomyopathy

• δct, transcript of interest minus gapdh control
• ace2, angiotensin i converting enzyme 2
• acei, angiotensin-converting enzyme inhibitor
• arb, angiotensin receptor blocker
• at1r, angiotensin type 1 receptor
• bp, blood pressure
• cdna, complementary dna
• chf, congestive heart failure
• covid-19, coronavirus disease 2019
• ecg, electrocardiogram
• gtp, guanosine triphosphate
• hcm, hypertrophic cardiomyopathy
• hrsace2, human recombinant soluble angiotensin i converting enzyme 2
• htn, hypertension
• icu, intensive care unit
• iqr, interquartile range
• lv, left ventricular
• mig, maximum instantaneous gradient
• mrna, messenger rna
• mybpc3, myosin binding protein c
• myh7, beta myosin heavy chain
• na, not available
• ns, not significant
• nyha, new york heart association
• qrt-pcr, quantitative real-time polymerase chain reaction
• raas, renin-angiotensin-aldosterone system
• sars-cov-2, severe acute respiratory syndrome coronavirus 2
• scd, sudden cardiac death
• utr, untranslated region

• Adolescent
• Adult
• Aged
• Angiotensin-Converting Enzyme 2
• Betacoronavirus
• COVID-19
• Cardiomyopathy, Hypertrophic/genetics
• Cardiomyopathy, Hypertrophic/metabolism
• Cardiomyopathy, Hypertrophic/virology
• Case-Control Studies
• Child
• Coronavirus Infections/complications
• Genotype
• Humans
• Middle Aged
• Myocardium/metabolism
• Pandemics
• Peptidyl-Dipeptidase A/genetics
• Peptidyl-Dipeptidase A/metabolism
• Pneumonia, Viral/complications
• RNA, Messenger/metabolism
• Real-Time Polymerase Chain Reaction
• SARS-CoV-2
• Young Adult

• R01 HL084553 NHLBI NIH HHS
• R01 HL133165 NHLBI NIH HHS