{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T14:48:57Z","timestamp":1780498137556,"version":"3.54.1"},"reference-count":100,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T00:00:00Z","timestamp":1690848000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>With the advent of next-generation whole genome sequencing, many variants of uncertain significance (VUS) have been identified in individuals suffering from inheritable hypertrophic cardiomyopathy (HCM). Unfortunately, this classification of a genetic variant results in ambiguity in interpretation, risk stratification, and clinical practice. Here, we aim to review some basic science methods to gain a more accurate characterization of VUS in HCM. Currently, many genomic data-based computational methods have been developed and validated against each other to provide a robust set of resources for researchers. With the continual improvement in computing speed and accuracy, in silico molecular dynamic simulations can also be applied in mutational studies and provide valuable mechanistic insights. In addition, high throughput <jats:italic>in vitro<\/jats:italic> screening can provide more biologically meaningful insights into the structural and functional effects of VUS. Lastly, multi-level mathematical modeling can predict how the mutations could cause clinically significant organ-level dysfunction. We discuss emerging technologies that will aid in better VUS characterization and offer a possible basic science workflow for exploring the pathogenicity of VUS in HCM. Although the focus of this mini review was on HCM, these basic science methods can be applied to research in dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), arrhythmogenic cardiomyopathy (ACM), or other genetic cardiomyopathies.<\/jats:p>","DOI":"10.3389\/fcvm.2023.1238515","type":"journal-article","created":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T16:20:23Z","timestamp":1690906823000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Basic science methods for the characterization of variants of uncertain significance in hypertrophic cardiomyopathy"],"prefix":"10.3389","volume":"10","author":[{"given":"Chang Yoon","family":"Doh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kampourakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth S.","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian E.","family":"Stelzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1016\/j.jacc.2015.07.074","article-title":"What is the true prevalence of hypertrophic cardiomyopathy?","volume":"66","author":"Baudhuin","year":"2015","journal-title":"J Am Coll Cardiol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"D789","DOI":"10.1093\/nar\/gku1205","article-title":"OMIM.Org: online mendelian inheritance in man (OMIM\u00ae), an online catalog of human genes and genetic disorders","volume":"43","author":"Amberger","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B3","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1161\/CIRCRESAHA.117.311059","article-title":"Hypertrophic cardiomyopathy","volume":"121","author":"Marian","year":"2017","journal-title":"Circ Res"},{"key":"B4","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1093\/cvr\/cvv025","article-title":"Genetic advances in sarcomeric cardiomyopathies: state of the art","volume":"105","author":"Ho","year":"2015","journal-title":"Cardiovasc Res"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2733","DOI":"10.1093\/eurheartj\/ehu284","article-title":"ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC)","volume":"35","author":"Elliott","year":"2014","journal-title":"Eur Heart J"},{"key":"B6","doi-asserted-by":"publisher","first-page":"195","DOI":"10.2147\/TACG.S49126","article-title":"Genetics of hypertrophic cardiomyopathy: advances and pitfalls in molecular diagnosis and therapy","volume":"7","author":"Roma-Rodrigues","year":"2014","journal-title":"Appl Clin Genet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1016\/j.jacc.2020.06.023","article-title":"Variable penetrance in hypertrophic cardiomyopathy","volume":"76","author":"Semsarian","year":"2020","journal-title":"J Am Coll Cardiol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.722340","article-title":"Hypertrophic cardiomyopathy: from phenotype and pathogenesis to treatment","author":"Cheng","year":"2021","journal-title":"Front Cardiovasc Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"Clinvar: improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.122.003704","article-title":"Prevalence and disease expression of pathogenic and likely pathogenic variants associated with inherited cardiomyopathies in the general population","volume":"15","author":"Bourfiss","year":"2022","journal-title":"Circ Genom Precis Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2022.975478","article-title":"Clinical significance of genetic variation in hypertrophic cardiomyopathy: comparison of computational tools to prioritize missense variants","volume":"9","author":"Barbosa","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"B12","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1161\/CIRCGEN.120.002929","article-title":"Spatial and functional distribution of MYBPC3 pathogenic variants and clinical outcomes in patients with hypertrophic cardiomyopathy","volume":"13","author":"Helms","year":"2020","journal-title":"Circ Genom Precis Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.yjmcc.2020.10.003","article-title":"Targeting the population for gene therapy with MYBPC3","volume":"150","author":"Carrier","year":"2021","journal-title":"J Mol Cell Cardiol"},{"key":"B14","author":"Gerull","year":""},{"key":"B15","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1161\/CIRCRESAHA.110.231670","article-title":"In the thick of it","volume":"108","author":"Harris","year":"2011","journal-title":"Circ Res"},{"key":"B16","doi-asserted-by":"publisher","first-page":"6701","DOI":"10.1073\/pnas.1606950113","article-title":"Multidimensional structure-function relationships in human \u03b2-cardiac myosin from population-scale genetic variation","volume":"113","author":"Homburger","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"key":"B17","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1136\/jmedgenet-2020-106922","article-title":"Data-driven modelling of mutational hotspots and in silico predictors in hypertrophic cardiomyopathy","volume":"58","author":"Waring","year":"2021","journal-title":"J Med Genet"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.24634","article-title":"Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes","author":"Alamo","year":"2017","journal-title":"Elife"},{"key":"B19","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"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","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1901","DOI":"10.1093\/eurheartj\/ehab895","article-title":"Interpretation and actionability of genetic variants in cardiomyopathies: a position statement from the European society of cardiology council on cardiovascular genomics","volume":"43","author":"Arbustini","year":"2022","journal-title":"Eur Heart J"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2227","DOI":"10.1161\/01.CIR.0000066323.15244.54","article-title":"Hypertrophic Cardiomyopathy","volume":"107","author":"Richard","year":"2003","journal-title":"Circulation"},{"key":"B22","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1161\/01.CIR.0000080896.52003.DF","article-title":"Prevalence and Spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy","volume":"108","author":"Van Driest","year":"2003","journal-title":"Circulation"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.116.001666","article-title":"Multiple gene variants in hypertrophic cardiomyopathy in the era of next-generation sequencing","volume":"10","author":"Burns","year":"2017","journal-title":"Circ Cardiovasc Genet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2715","DOI":"10.1093\/eurheartj\/ehq271","article-title":"Genetic counselling and testing in cardiomyopathies: a position statement of the European society of cardiology working group on myocardial and pericardial diseases","volume":"31","author":"Charron","year":"2010","journal-title":"Eur Heart J"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1161\/CIRCULATIONAHA.117.033200","article-title":"Genotype and lifetime burden of disease in hypertrophic cardiomyopathy","volume":"138","author":"Ho","year":"2018","journal-title":"Circulation"},{"key":"B26","doi-asserted-by":"publisher","first-page":"10401","DOI":"10.3390\/ijms221910401","article-title":"Genetic testing in patients with hypertrophic cardiomyopathy","volume":"22","author":"Bonaventura","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B27","doi-asserted-by":"publisher","first-page":"3266","DOI":"10.1038\/s41598-019-39796-w","article-title":"Selecting variants of unknown significance through network-based gene-association significantly improves risk prediction for disease-control cohorts","volume":"9","author":"Oulas","year":"2019","journal-title":"Sci Rep"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1101\/mcs.a006196","article-title":"Computational and experimental methods for classifying variants of unknown clinical significance","volume":"8","author":"Spielmann","year":"2022","journal-title":"Cold Spring Harb Mol Case Stud"},{"key":"B29","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1111\/cts.12440","article-title":"High-throughput assays to assess the functional impact of genetic variants: a road towards genomic-driven medicine","volume":"10","author":"Ipe","year":"2017","journal-title":"Clin Transl Sci"},{"key":"B30","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1002\/humu.10212","article-title":"Human gene mutation database (HGMD \u00ae): 2003 update","volume":"21","author":"Stenson","year":"2003","journal-title":"Hum Mutat"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.981005","article-title":"Computational approaches for predicting variant impact: an overview from resources, principles to applications","volume":"13","author":"Liu","year":"2022","journal-title":"Front Genet"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.049510","article-title":"Interpreting protein variant effects with computational predictors and deep mutational scanning","volume":"15","author":"Livesey","year":"2022","journal-title":"Dis Model Mech"},{"key":"B33","doi-asserted-by":"publisher","first-page":"606","DOI":"10.3390\/ijms22020606","article-title":"SAAFEC-SEQ: a sequence-based method for predicting the effect of single point mutations on protein thermodynamic stability","volume":"22","author":"Li","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B34","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/s41436-020-00972-3","article-title":"Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions","volume":"23","author":"Zhang","year":"2021","journal-title":"Genet Med"},{"key":"B35","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.ajhg.2011.01.011","article-title":"Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy","volume":"88","author":"Jordan","year":"2011","journal-title":"Am J Hum Genet"},{"key":"B36","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s13073-019-0616-z","article-title":"Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: the case of hypertrophic cardiomyopathy","volume":"11","author":"Walsh","year":"2019","journal-title":"Genome Med"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2936","DOI":"10.1093\/bioinformatics\/btw361","article-title":"STRUM: structure-based prediction of protein stability changes upon single-point mutation","volume":"32","author":"Quan","year":"2016","journal-title":"Bioinformatics"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1038\/s41436-021-01134-9","article-title":"Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation","volume":"23","author":"Thompson","year":"2021","journal-title":"Genet Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.yjmcc.2018.04.006","article-title":"Neural\/Bayes network predictor for inheritable cardiac disease pathogenicity and phenotype","volume":"119","author":"Burghardt","year":"2018","journal-title":"J Mol Cell Cardiol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"279","DOI":"10.3390\/life12020279","article-title":"Artificial intelligence and cardiovascular genetics","volume":"12","author":"Krittanawong","year":"2022","journal-title":"Life"},{"key":"B41","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/j.bbadis.2019.01.007","article-title":"The HCM-causing Y235S cMyBPC mutation accelerates contractile function by altering C1 domain structure","volume":"1865","author":"Doh","year":"2019","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1916","DOI":"10.1080\/07391102.2016.1199329","article-title":"Impact of disease-causing mutations on inter-domain interactions in cMyBP-C: a steered molecular dynamics study","volume":"35","author":"Krishnamoorthy","year":"2017","journal-title":"J Biomol Struct Dyn"},{"key":"B43","doi-asserted-by":"publisher","first-page":"18","DOI":"10.3390\/ijms24010018","article-title":"De Novo Asp219Val mutation in cardiac tropomyosin associated with hypertrophic cardiomyopathy","volume":"24","author":"Tsaturyan","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1093\/pnasnexus\/pgad011","article-title":"Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215l","volume":"2","author":"Halder","year":"2023","journal-title":"PNAS Nexus"},{"key":"B45","doi-asserted-by":"publisher","first-page":"e1004728","DOI":"10.1371\/journal.pcbi.1004728","article-title":"Ensembler: enabling high-throughput molecular simulations at the superfamily scale","volume":"12","author":"Parton","year":"2016","journal-title":"PLoS Comput Biol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s13321-020-00451-6","article-title":"Intuitive, reproducible high-throughput molecular dynamics in galaxy: a tutorial","volume":"12","author":"Bray","year":"2020","journal-title":"J Cheminform"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1021\/acs.jctc.6b00049","article-title":"HTMD: high-throughput molecular dynamics for molecular discovery","volume":"12","author":"Doerr","year":"2016","journal-title":"J Chem Theory Comput"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1016\/j.drudis.2012.03.017","article-title":"High-throughput molecular dynamics: the powerful new tool for drug discovery","volume":"17","author":"Harvey","year":"2012","journal-title":"Drug Discov Today"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.154350","article-title":"Computational and biophysical determination of pathogenicity of variants of unknown significance in cardiac thin filament","volume":"6","author":"Mason","year":"2021","journal-title":"JCI Insight"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.1010327","article-title":"Insights on variant analysis in silico tools for pathogenicity prediction","volume":"13","author":"de Garcia","year":"2022","journal-title":"Front Genet"},{"key":"B51","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1007\/s00401-020-02257-0","article-title":"Making sense of missense variants in TTN-related congenital myopathies","volume":"141","author":"Rees","year":"2021","journal-title":"Acta Neuropathol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"9071","DOI":"10.1038\/s41598-017-08664-w","article-title":"A method for rapid high-throughput biophysical analysis of proteins","volume":"7","author":"Perez-Riba","year":"2017","journal-title":"Sci Rep"},{"key":"B53","doi-asserted-by":"publisher","first-page":"101485","DOI":"10.1016\/j.jbc.2021.101485","article-title":"Microscale thermophoresis suggests a new model of regulation of cardiac myosin function via interaction with cardiac myosin-binding protein C","volume":"298","author":"Ponnam","year":"2022","journal-title":"J Biol Chem"},{"key":"B54","doi-asserted-by":"publisher","first-page":"15485","DOI":"10.1073\/pnas.1903033116","article-title":"Site-specific phosphorylation of myosin binding protein-C coordinates thin and thick filament activation in cardiac muscle","volume":"116","author":"Ponnam","year":"2019","journal-title":"Proc Natl Acad Sci USA"},{"key":"B55","doi-asserted-by":"publisher","first-page":"2","DOI":"10.3389\/fphys.2013.00336","article-title":"Novel control of cardiac myofilament response to calcium by S-glutathionylation at specific sites of myosin binding protein C","volume":"4","author":"Patel","year":"2013","journal-title":"Front Physiol"},{"key":"B56","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.1161\/CIRCRESAHA.116.305372","article-title":"Proteotoxicity and cardiac dysfunction","volume":"116","author":"McLendon","year":"2015","journal-title":"Circ Res"},{"key":"B57","doi-asserted-by":"publisher","first-page":"6492","DOI":"10.1021\/acsomega.8b03340","article-title":"Proof of principle that molecular modeling followed by a biophysical experiment can develop small molecules that restore function to the cardiac thin filament in the presence of cardiomyopathic mutations","volume":"4","author":"Szatkowski","year":"2019","journal-title":"ACS Omega"},{"key":"B58","doi-asserted-by":"publisher","first-page":"107856","DOI":"10.1016\/j.jsb.2022.107856","article-title":"Molecular characterization of linker and loop-mediated structural modulation and hinge motion in the C4-C5 domains of cMyBPC","volume":"214","author":"Doh","year":"2022","journal-title":"J Struct Biol"},{"key":"B59","doi-asserted-by":"publisher","first-page":"100840","DOI":"10.1016\/j.jbc.2021.100840","article-title":"Cardiac myosin-binding protein C interaction with actin is inhibited by compounds identified in a high-throughput fluorescence lifetime screen","volume":"297","author":"Bunch","year":"2021","journal-title":"J Biol Chem"},{"key":"B60","doi-asserted-by":"publisher","first-page":"H1179","DOI":"10.1152\/ajpheart.00686.2017","article-title":"The HCM-linked W792R mutation in cardiac myosin-binding protein C reduces C6 FnIII domain stability","volume":"314","author":"Smelter","year":"2018","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B61","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1007\/s12265-020-09959-6","article-title":"Protein thermodynamic destabilization in the assessment of pathogenicity of a variant of uncertain significance in cardiac myosin binding protein C","volume":"13","author":"Pricolo","year":"2020","journal-title":"J Cardiovasc Transl Res"},{"key":"B62","doi-asserted-by":"publisher","first-page":"100854","DOI":"10.1016\/j.jbc.2021.100854","article-title":"Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy","volume":"297","author":"Suay-Corredera","year":"2021","journal-title":"J Biol Chem"},{"key":"B63","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1089\/adt.2011.0380","article-title":"Molecular interaction studies using microscale thermophoresis","volume":"9","author":"Jerabek-Willemsen","year":"2011","journal-title":"Assay Drug Dev Technol"},{"key":"B64","doi-asserted-by":"publisher","first-page":"042001","DOI":"10.1088\/2050-6120\/ac82a6","article-title":"Microscale thermophoresis as a powerful growing analytical technique for the investigation of biomolecular interaction and the determination of binding parameters","volume":"10","author":"El Deeb","year":"2022","journal-title":"Methods Appl Fluoresc"},{"key":"B65","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/nsmb.3408","article-title":"The myosin mesa and the basis of hypercontractility caused by hypertrophic cardiomyopathy mutations","volume":"24","author":"Nag","year":"2017","journal-title":"Nat Struct Mol Biol"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aax0069","article-title":"The hypertrophic cardiomyopathy mutations R403Q and R663H increase the number of myosin heads available to interact with actin","author":"Sarkar","year":"2020","journal-title":"Sci Adv"},{"key":"B67","doi-asserted-by":"publisher","first-page":"17383","DOI":"10.1074\/jbc.RA120.015632","article-title":"FRET And optical trapping reveal mechanisms of actin activation of the power stroke and phosphate release in myosin V","volume":"295","author":"Gunther","year":"2020","journal-title":"J Biol Chem"},{"key":"B68","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.yjmcc.2022.02.005","article-title":"Human cardiac myosin-binding protein C phosphorylation- and mutation-dependent structural dynamics monitored by time-resolved FRET","volume":"166","author":"Kanassatega","year":"2022","journal-title":"J Mol Cell Cardiol"},{"key":"B69","doi-asserted-by":"publisher","first-page":"2023.04.03.535496","DOI":"10.1101\/2023.04.03.535496","article-title":"Drug discovery for heart failure targeting myosin-binding protein C","author":"Bunch","year":"2023","journal-title":"bioRxiv"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.3791\/60017","article-title":"A semi-high-throughput adaptation of the NADH-coupled ATPase assay for screening small molecule inhibitors","volume":"150","author":"Radnai","year":"2019","journal-title":"J Visualized Exp"},{"key":"B71","doi-asserted-by":"publisher","first-page":"6717","DOI":"10.1021\/bi500787f","article-title":"Modulation of thin filament activation of myosin ATP hydrolysis by N-terminal domains of cardiac myosin binding protein-C","volume":"53","author":"Belknap","year":"2014","journal-title":"Biochemistry"},{"key":"B72","doi-asserted-by":"publisher","first-page":"2666","DOI":"10.1161\/CIRCULATIONAHA.117.032273","article-title":"Determining the pathogenicity of a genomic variant of uncertain significance using CRISPR\/Cas9 and human-induced pluripotent stem cells","volume":"138","author":"Ma","year":"2018","journal-title":"Circulation"},{"key":"B73","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1016\/j.tig.2021.08.009","article-title":"Deciphering pathogenicity of variants of uncertain significance with CRISPR-edited iPSCs","volume":"37","author":"Guo","year":"2021","journal-title":"Trends Genet"},{"key":"B74","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1016\/j.jcyt.2020.06.008","article-title":"High-throughput assessment of mutations generated by genome editing in induced pluripotent stem cells by high-resolution melting analysis","volume":"22","author":"Pham","year":"2020","journal-title":"Cytotherapy"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.79208","article-title":"Highly efficient generation of isogenic pluripotent stem cell models using prime editing","volume":"11","author":"Li","year":"2022","journal-title":"Elife"},{"key":"B76","doi-asserted-by":"publisher","first-page":"3076","DOI":"10.1016\/j.stemcr.2021.11.004","article-title":"Robotic high-throughput biomanufacturing and functional differentiation of human pluripotent stem cells","volume":"16","author":"Tristan","year":"2021","journal-title":"Stem Cell Rep"},{"key":"B77","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1038\/nmeth.3507","article-title":"Automated, high-throughput derivation, characterization and differentiation of induced pluripotent stem cells","volume":"12","author":"Paull","year":"2015","journal-title":"Nat Methods"},{"key":"B78","doi-asserted-by":"publisher","first-page":"3879","DOI":"10.1093\/eurheartj\/ehy249","article-title":"CRISPR\/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy","volume":"39","author":"Mosqueira","year":"2018","journal-title":"Eur Heart J"},{"key":"B79","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1161\/CIRCRESAHA.118.314505","article-title":"Sarctrack","volume":"124","author":"Toepfer","year":"2019","journal-title":"Circ Res"},{"key":"B80","doi-asserted-by":"publisher","first-page":"4381","DOI":"10.3390\/ijms20184381","article-title":"Human induced pluripotent stem-cell-derived cardiomyocytes as models for genetic cardiomyopathies","volume":"20","author":"Brodehl","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.133782","article-title":"Effects of MYBPC3 loss-of-function mutations preceding hypertrophic cardiomyopathy","volume":"5","author":"Helms","year":"2020","journal-title":"JCI Insight"},{"key":"B82","doi-asserted-by":"publisher","first-page":"3893","DOI":"10.1093\/eurheartj\/ehy388","article-title":"Disease modelling and drug discovery for hypertrophic cardiomyopathy using pluripotent stem cells: how far have we come?","volume":"39","author":"Lam","year":"2018","journal-title":"Eur Heart J"},{"key":"B83","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/S0096-4174(18)30128-8","article-title":"Muscle structure and theories of contraction","volume":"7","author":"Huxley","year":"1957","journal-title":"Prog Biophys Biophys Chem"},{"key":"B84","doi-asserted-by":"publisher","first-page":"H779","DOI":"10.1152\/ajpheart.1994.267.2.H779","article-title":"Mechanical regulation of cardiac muscle by coupling calcium kinetics with cross-bridge cycling: a dynamic model","volume":"267","author":"Landesberg","year":"1994","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B85","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.yjmcc.2018.11.015","article-title":"A short history of the development of mathematical models of cardiac mechanics","volume":"127","author":"Niederer","year":"2019","journal-title":"J Mol Cell Cardiol"},{"key":"B86","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1007\/BF02364118","article-title":"A model of the mechanics of the left ventricle","volume":"7","author":"Arts","year":"1979","journal-title":"Ann Biomed Eng"},{"key":"B87","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.abb.2019.01.006","article-title":"Closing the therapeutic loop","volume":"663","author":"Campbell","year":"2019","journal-title":"Arch Biochem Biophys"},{"key":"B88","doi-asserted-by":"publisher","first-page":"2023.04.11.536387","DOI":"10.1101\/2023.04.11.536387","article-title":"In situ structures from relaxed cardiac myofibrils reveal the organization of the muscle thick filament","author":"Tamborrini","year":"2023","journal-title":"bioRxiv"},{"key":"B89","doi-asserted-by":"publisher","first-page":"2023.04.11.536274","DOI":"10.1101\/2023.04.11.536274","article-title":"Cryo-EM structure of the human cardiac myosin filament","author":"Dutta","year":"2023","journal-title":"bioRxiv"},{"key":"B90","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.bpj.2014.11.1852","article-title":"Effects of cardiac myosin binding protein-C on actin motility are explained with a drag-activation-competition model","volume":"108","author":"Walcott","year":"2015","journal-title":"Biophys J"},{"key":"B91","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1016\/S0006-3495(98)77875-0","article-title":"Compliant realignment of binding sites in muscle: transient behavior and mechanical tuning","volume":"74","author":"Daniel","year":"1998","journal-title":"Biophys J"},{"key":"B92","doi-asserted-by":"publisher","first-page":"1624","DOI":"10.1007\/s10439-008-9536-6","article-title":"Towards a unified theory of muscle contraction. I: foundations","volume":"36","author":"Smith","year":"2008","journal-title":"Ann Biomed Eng"},{"key":"B93","doi-asserted-by":"publisher","first-page":"e115","DOI":"10.1371\/journal.pcbi.0030115","article-title":"Sarcomere lattice geometry influences cooperative myosin binding in muscle","volume":"3","author":"Tanner","year":"2007","journal-title":"PLoS Comput Biol"},{"key":"B94","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.bpj.2021.12.021","article-title":"Fibersim: a flexible open-source model of myofilament-level contraction","volume":"121","author":"Kosta","year":"2022","journal-title":"Biophys J"},{"key":"B95","doi-asserted-by":"publisher","first-page":"2234","DOI":"10.1007\/s10439-009-9774-2","article-title":"Three-Wall segment (TriSeg) model describing mechanics and hemodynamics of ventricular interaction","volume":"37","author":"Lumens","year":"2009","journal-title":"Ann Biomed Eng"},{"key":"B96","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1007\/s12551-021-00826-5","article-title":"Multiscale simulations of left ventricular growth and remodeling","volume":"13","author":"Sharifi","year":"2021","journal-title":"Biophys Rev"},{"key":"B97","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1016\/j.cell.2016.04.002","article-title":"A tension-based model distinguishes hypertrophic versus dilated cardiomyopathy","volume":"165","author":"Davis","year":"2016","journal-title":"Cell"},{"key":"B98","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1177\/07487304221075002","article-title":"High-throughput genetically modified animal experiments achieved by next-generation mammalian genetics","volume":"37","author":"Minami","year":"2022","journal-title":"J Biol Rhythms"},{"key":"B99","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1097\/00001573-200005000-00012","article-title":"Animal models of hypertrophic cardiomyopathy","volume":"15","author":"Maass","year":"2000","journal-title":"Curr Opin Cardiol"},{"key":"B100","doi-asserted-by":"crossref","DOI":"10.5772\/intechopen.89033","article-title":"Animal models of cardiomyopathies","volume-title":"Animal models in medicine and biology","author":"Purevjav","year":"2020"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2023.1238515\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T16:20:28Z","timestamp":1690906828000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2023.1238515\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,1]]},"references-count":100,"alternative-id":["10.3389\/fcvm.2023.1238515"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2023.1238515","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,1]]},"article-number":"1238515"}}