Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with an estimated prevalence of up to 1 in 200 individuals. In the majority of cases, HCM is considered a Mendelian disease, with mainly autosomal dominant inheritance. Most pathogenic variants are usually detected in genes for sarcomeric proteins. Nowadays, the genetic basis of HCM is believed to be rather complex. Thousands of mutations in more than 60 genes have been described in association with HCM. Nevertheless, screening large numbers of genes results in the identification of many genetic variants of uncertain significance and makes the interpretation of the results difficult. Patients lacking a pathogenic variant are now believed to have non-Mendelian HCM and probably have a better prognosis than patients with sarcomeric pathogenic mutations. Identifying the genetic basis of HCM creates remarkable opportunities to understand how the disease develops, and by extension, how to disrupt the disease progression in the future. The aim of this review is to discuss the brief history and recent advances in the genetics of HCM and the application of molecular genetic testing into common clinical practice.

Department of Cardiology Motol University Hospital 2nd Faculty of Medicine Charles University 5 Uvalu 84 15006 Prague Czech Republic

See more in PubMed

Elliott P.M., Anastasakis A., Borger M., Borggrefe M., Cecchi F., Charron P., Hagege A., Lafont A., Limongelli G., Mahrholdt H., et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur. Heart J. 2014;35:2733–2779. doi: 10.5603/KP.2014.0212. PubMed DOI

Veselka J., Anavekar N.S., Charron P. Hypertrophic obstructive cardiomyopathy. Lancet. 2016;389:1253–1267. doi: 10.1016/S0140-6736(16)31321-6. PubMed DOI

Richard P., Charron P., Carrier L., Ledeuil C., Cheav T., Pichereau C., Benaiche A., Isnard R., Dubourg O., Burban M., et al. Hypertrophic Cardiomyopathy. Circulation. 2003;107:2227–2232. doi: 10.1161/01.CIR.0000066323.15244.54. PubMed DOI

Maron B.J., Doerer J.J., Haas T.S., Tierney D., Mueller F.O. Sudden Deaths in Young Competitive Athletes. Circulation. 2009;119:1085–1092. doi: 10.1161/CIRCULATIONAHA.108.804617. PubMed DOI

Semsarian C., Ingles J., Maron M.S., Maron B.J. New Perspectives on the Prevalence of Hypertrophic Cardiomyopathy. J. Am. Coll. Cardiol. 2015;65:1249–1254. doi: 10.1016/j.jacc.2015.01.019. PubMed DOI

Ackerman M., Atkins D.L., Triedman J.K. Sudden Cardiac Death in the Young. Circulation. 2016;133:1006–1026. doi: 10.1161/CIRCULATIONAHA.115.020254. PubMed DOI PMC

Teare D. Asymmetrical Hypertrophy of the Heart in Young Adults. Heart. 1958;20:1–8. doi: 10.1136/hrt.20.1.1. PubMed DOI PMC

Geisterfer-Lowrance A.A., Kass S., Tanigawa G., Vosberg H.-P., McKenna W., Seidman C.E., Seidman J. A molecular basis for familial hypertrophic cardiomyopathy: A β cardiac myosin heavy chain gene missense mutation. Cell. 1990;62:999–1006. doi: 10.1016/0092-8674(90)90274-I. PubMed DOI

Jarcho J.A., McKenna W.J., Pare J.P., Solomon S.D., Holcombe R.F., Dickie S., Levi T., Donis-Keller H., Seidman J., Seidman C.E. Mapping a Gene for Familial Hypertrophic Cardiomyopathy to Chromosome 14q1. N. Engl. J. Med. 1989;321:1372–1378. doi: 10.1056/NEJM198911163212005. PubMed DOI

Ho C.Y., Charron P., Richard P., Girolami F., Van Spaendonck-Zwarts K.Y., Pinto Y. Genetic advances in sarcomeric cardiomyopathies: State of the art. Cardiovasc. Res. 2015;105:397–408. doi: 10.1093/cvr/cvv025. PubMed DOI PMC

Ingles J., Goldstein J., Thaxton C., Caleshu C., Corty E.W., Crowley S.B., Dougherty K., Harrison S.M., McGlaughon J., Milko L.V., et al. Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes. Circ. Genom. Precis. Med. 2019;12:e002460. doi: 10.1161/CIRCGEN.119.002460. PubMed DOI PMC

Lopes L., Syrris P., Guttmann O.P., O’Mahony C., Tang H.C., Dalageorgou C., Jenkins S., Hubank M., Monserrat L., McKenna W.J., et al. Novel genotype–phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2014;101:294–301. doi: 10.1136/heartjnl-2014-306387. PubMed DOI PMC

Walsh R., Buchan R., Wilk A., John S., Felkin L.E., Thomson K., Chiaw T.H., Loong C.C.W., Pua C.J., Raphael C., et al. Defining the genetic architecture of hypertrophic cardiomyopathy: Re-evaluating the role of non-sarcomeric genes. Eur. Heart J. 2017;38:3461–3468. doi: 10.1093/eurheartj/ehw603. PubMed DOI PMC

Thomson K.L., NIHR BioResource—Rare Diseases Consortium. Ormondroyd E., Harper A.R., Dent T., McGuire K., Baksi J., Blair E., Brennan P., Buchan R., et al. Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield. Genet. Med. 2018;21:1576–1584. doi: 10.1038/s41436-018-0375-z. PubMed DOI PMC

Mazzarotto F., Olivotto I., Boschi B., Girolami F., Poggesi C., Barton P., Walsh R. Contemporary Insights Into the Genetics of Hypertrophic Cardiomyopathy: Toward a New Era in Clinical Testing? J. Am. Heart Assoc. 2020;9:e015473. doi: 10.1161/JAHA.119.015473. PubMed DOI PMC

Lopes L.R., Garcia-Hernández S., Lorenzini M., Futema M., Chumakova O., Zateyshchikov D., Isidoro-Garcia M., Villacorta E., Escobar-Lopez L., Garcia-Pavia P., et al. Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy. Eur. Heart J. 2021;42:3063–3073. doi: 10.1093/eurheartj/ehab424. PubMed DOI PMC

Harper A.R., HCMR Investigators. Goel A., Grace C., Thomson K.L., Petersen S.E., Xu X., Waring A., Ormondroyd E., Kramer C.M., et al. Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. Nat. Genet. 2021;53:135–142. doi: 10.1038/s41588-020-00764-0. PubMed DOI PMC

Ochoa J.P., Sabater-Molina M., García-Pinilla J.M., Mogensen J., Restrepo-Córdoba A., Palomino-Doza J., Villacorta E., Martinez-Moreno M., Ramos-Maqueda J., Zorio E., et al. Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy. J. Am. Coll. Cardiol. 2018;72:2457–2467. doi: 10.1016/j.jacc.2018.10.001. PubMed DOI

Walsh R., Offerhaus J.A., Tadros R., Bezzina C.R. Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies. Nat. Rev. Cardiol. 2021 doi: 10.1038/s41569-021-00608-2. PubMed DOI

Tadros R., Francis C., Xu X., Vermeer A.M.C., Harper A.R., Huurman R., Bisabu K.K., Walsh R., Hoorntje E.T., Rijdt W.P.T., et al. Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. Nat. Genet. 2021;53:128–134. doi: 10.1038/s41588-020-00762-2. PubMed DOI PMC

Maron B.J., Maron M.S., Semsarian C. Genetics of Hypertrophic Cardiomyopathy After 20 Years. J. Am. Coll. Cardiol. 2012;60:705–715. doi: 10.1016/j.jacc.2012.02.068. PubMed DOI

Alfares A.A., Kelly M.A., McDermott G., Funke B.H., Lebo M.S., Baxter S.B., Shen J., McLaughlin H.M., Clark E.H., Babb L.J., et al. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: Expanded panels offer limited additional sensitivity. Genet. Med. 2015;17:880–888. doi: 10.1038/gim.2014.205. PubMed DOI

Ingles J., Burns C., Barratt A., Semsarian C. Application of Genetic Testing in Hypertrophic Cardiomyopathy for Preclinical Disease Detection. Circ. Cardiovasc. Genet. 2015;8:852–859. doi: 10.1161/CIRCGENETICS.115.001093. PubMed DOI

Sabater-Molina M., Pérez-Sánchez I., Del Rincón J.H., Gimeno J. Genetics of hypertrophic cardiomyopathy: A review of current state. Clin. Genet. 2017;93:3–14. doi: 10.1111/cge.13027. PubMed DOI

Online Mendelian Inheritance in Man. [(accessed on 28 August 2021)]. Available online: www.omim.org.

McNally E., Dellefave L. Sarcomere Mutations in Cardiogenesis and Ventricular Noncompaction. Trends Cardiovasc. Med. 2009;19:17–21. doi: 10.1016/j.tcm.2009.03.003. PubMed DOI

Mogensen J., Kubo T., Duque M., Uribe W., Shaw A., Murphy R., Gimeno J.R., Elliott P., McKenna W.J. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J. Clin. Investig. 2003;111:209–216. doi: 10.1172/JCI200316336. PubMed DOI PMC

Cimiotti D., Budde H., Hassoun R., Jaquet K. Genetic Restrictive Cardiomyopathy: Causes and Consequences—An Integrative Approach. Int. J. Mol. Sci. 2021;22:558. doi: 10.3390/ijms22020558. PubMed DOI PMC

Bortot B., Athanasakis E., Brun F., Rizzotti D., Mestroni L., Sinagra G., Severini G.M. High-throughput Genotyping Robot-assisted Method for Mutation Detection in Patients With Hypertrophic Cardiomyopathy. Diagn. Mol. Pathol. 2011;20:175–179. doi: 10.1097/PDM.0b013e31820b34fb. PubMed DOI

Fokstuen S., Munoz A., Melacini P., Iliceto S., Perrot A., Ozcelik C., Jeanrenaud X., Rieubland C., Farr M., Faber L., et al. Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice. J. Med. Genet. 2011;48:572–576. doi: 10.1136/jmg.2010.083345. PubMed DOI

Meder B., Haas J., Keller A., Heid C., Just S., Borries A., Boisguerin V., Scharfenberger-Schmeer M., Stähler P., Beier M., et al. Targeted Next-Generation Sequencing for the Molecular Genetic Diagnostics of Cardiomyopathies. Circ. Cardiovasc. Genet. 2011;4:110–122. doi: 10.1161/CIRCGENETICS.110.958322. PubMed DOI

Charron P., Villard E., Sébillon P., Laforêt P., Maisonobe T., Duboscq-Bidot L., Romero N., Drouin-Garraud V., Frébourg T., Richard P., et al. Danon’s disease as a cause of hypertrophic cardiomyopathy: A systematic survey. Heart. 2004;90:842–846. doi: 10.1136/hrt.2003.029504. PubMed DOI PMC

Bernstein H.S., Bishop D.F., Astrin K.H., Kornreich R., Eng C.M., Sakuraba H., Desnick R.J. Fabry disease: Six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene. J. Clin. Investig. 1989;83:1390–1399. doi: 10.1172/JCI114027. PubMed DOI PMC

Martiniuk F., Mehler M., Bodkin M., Tzall S., Hirschhorn K., Zhong N., Hirschhorn R. Identification of a Missense Mutation in an Adult-Onset Patient with Glycogenosis Type II Expressing Only One Allele. DNA Cell Biol. 1991;10:681–687. doi: 10.1089/dna.1991.10.681. PubMed DOI

Martiniuk F., Mehler M., Pellicer A., Tzall S., La Badie G., Hobart C., Ellenbogen A., Hirschhorn R. Isolation of a cDNA for human acid alpha-glucosidase and detection of genetic heterogeneity for mRNA in three alpha-glucosidase-deficient patients. Proc. Natl. Acad. Sci. USA. 1986;83:9641–9644. doi: 10.1073/pnas.83.24.9641. PubMed DOI PMC

Van der Ploeg A.T., Hoefsloot L.H., Hoogeveen-Westerveld M., Petersen E.M., Reuser A.J. Glycogenosis type II: Protein and DNA analysis in five South African families from various ethnic origins. Am. J. Hum. Gen. 1989;44:787–793. PubMed PMC

Genomes Project. [(accessed on 28 August 2021)]. Available online: http://www.internationalgenome.org/

Exome Aggregation Consortium. [(accessed on 28 August 2021)]. Available online: http://exac.broadinstitute.org/

Exome Sequencing Project. [(accessed on 28 August 2021)]. Available online: http://evs.gs.washington.edu/EVS/

ClinVar. [(accessed on 28 August 2021)]; Available online: https://www.ncbi.nlm.nih.gov/clinvar.

Human Gene Mutation Database. [(accessed on 28 August 2021)]. Available online: http://www.hgmd.cf.ac.uk/ac/index.php.

Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J., Grody W.W., Hegde M., Lyon E., Spector E., 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;17:405–423. doi: 10.1038/gim.2015.30. PubMed DOI PMC

Lahrouchi N., Raju H., Lodder E.M., Papatheodorou E., Miles C., Ware J.S., Papadakis M., Tadros R., Cole D., Skinner J.R., et al. The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy. Eur. J. Hum. Genet. 2019;28:17–22. doi: 10.1038/s41431-019-0500-8. PubMed DOI PMC

Writing Committee Members. Ommen S.R., Mital S., Burke M.A., Day S.M., Deswal A., Elliott P., Evanovich L.L., Hung J., Joglar J.A., et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients with Hypertrophic Cardiomyopathy. Circulation. 2020;142 doi: 10.1161/cir.0000000000000937. PubMed DOI

Cardoso B., Gomes I., Loureiro P., Trigo C., Pinto F.F. Diagnóstico clínico e genético de miocardiopatia hipertrófica familiar: Resultados em cardiologia pediátrica. Rev. Port. Cardiol. 2017;36:155–165. doi: 10.1016/j.repc.2016.09.009. PubMed DOI

Jensen M.K., Havndrup O., Christiansen M., Andersen P.S., Diness B., Axelsson A., Skovby F., Køber L., Bundgaard H. Penetrance of Hypertrophic Cardiomyopathy in Children and Adolescents. Circulation. 2013;127:48–54. doi: 10.1161/CIRCULATIONAHA.111.090514. PubMed DOI

Hershberger R.E., Givertz M.M., Ho C.Y., Judge D., Kantor P.F., McBride K.L., Morales A., Taylor M.R., Vatta M., Ware S.M. Genetic Evaluation of Cardiomyopathy—A Heart Failure Society of America Practice Guideline. J. Card. Fail. 2018;24:281–302. doi: 10.1016/j.cardfail.2018.03.004. PubMed DOI PMC

Moore B., Semsarian C., Chan K.H., Sy R.W. Sudden Cardiac Death and Ventricular Arrhythmias in Hypertrophic Cardiomyopathy. Heart Lung Circ. 2018;28:146–154. doi: 10.1016/j.hlc.2018.07.019. PubMed DOI

Priori S.G., Blomström-Lundqvist C., Mazzanti A., Blom N., Borggrefe M., Camm J., Elliott P., Fitzsimons D., Hatala R., Hindricks G., et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Europace. 2015;17:1601–1687. doi: 10.1093/europace/euv319. PubMed DOI

Olivotto I., Girolami F., Ackerman M.J., Nistri S., Bos J.M., Zachara E., Ommen S.R., Theis J.L., Vaubel R.A., Re F., et al. Myofilament Protein Gene Mutation Screening and Outcome of Patients With Hypertrophic Cardiomyopathy. Mayo Clin. Proc. 2008;83:630–638. doi: 10.1016/S0025-6196(11)60890-2. PubMed DOI

Varnava A.M., Elliott P.M., Baboonian C., Davison F., Davies M.J., McKenna W.J. Hypertrophic Cardiomyopathy. Circulation. 2001;104:1380–1384. doi: 10.1161/hc3701.095952. PubMed DOI

Maron B.J., Yeates L., Semsarian C. Clinical Challenges of Genotype Positive (+)–Phenotype Negative (−) Family Members in Hypertrophic Cardiomyopathy. Am. J. Cardiol. 2011;107:604–608. doi: 10.1016/j.amjcard.2010.10.022. PubMed DOI

Ho C.Y. Genetics and Clinical Destiny: Improving Care in Hypertrophic Cardiomyopathy. Circulation. 2010;122:2430–2440. doi: 10.1161/CIRCULATIONAHA.110.978924. PubMed DOI PMC

Maurizi N., Michels M., Rowin E.J., Semsarian C., Girolami F., Tomberli B., Cecchi F., Maron M.S., Olivotto I., Maron B.J. Clinical Course and Significance of Hypertrophic Cardiomyopathy Without Left Ventricular Hypertrophy. Circulation. 2019;139:830–833. doi: 10.1161/CIRCULATIONAHA.118.037264. PubMed DOI

Charron P., Carrier L., Dubourg O., Tesson F., Desnos M., Richard P., Bonne G., Guicheney P., Hainque B., Bouhour J.B., et al. Penetrance of familial hypertrophic cardiomyopathy. Genet. Couns. 1997;8:107–114. PubMed

Bos J.M., Will M.L., Gersh B.J., Kruisselbrink T.M., Ommen S.R., Ackerman M.J. Characterization of a Phenotype-Based Genetic Test Prediction Score for Unrelated Patients With Hypertrophic Cardiomyopathy. Mayo Clin. Proc. 2014;89:727–737. doi: 10.1016/j.mayocp.2014.01.025. PubMed DOI PMC

Bonaventura J., Norambuena P., Tomašov P., Jindrová D., Šedivá H., Jr M.M., Veselka J., Macek M. The utility of the Mayo Score for predicting the yield of genetic testing in patients with hypertrophic cardiomyopathy. Arch. Med Sci. 2019;15:641–649. doi: 10.5114/aoms.2018.78767. PubMed DOI PMC

Andersen P.S., Havndrup O., Hougs L., Sørensen K.M., Jensen M.K., Larsen L.A., Hedley P., Thomsen A., Moolman-Smook J., Christiansen M., et al. Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives. Hum. Mutat. 2008;30:363–370. doi: 10.1002/humu.20862. PubMed DOI

Van Driest S.L., Ommen S.R., Tajik A.J., Gersh B.J., Ackerman M.J. Yield of Genetic Testing in Hypertrophic Cardiomyopathy. Mayo Clin. Proc. 2005;80:739–744. doi: 10.1016/S0025-6196(11)61527-9. PubMed DOI

Murphy S.L., Anderson J., Kapplinger J.D., Kruisselbrink T.M., Gersh B.J., Ommen S.R., Ackerman M.J., Bos J.M. Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy. J. Cardiovasc. Transl. Res. 2016;9:153–161. doi: 10.1007/s12265-016-9681-5. PubMed DOI PMC

Page S.P., Kounas S., Syrris P., Christiansen M., Frank-Hansen R., Andersen P.S., Elliott P.M., McKenna W.J. Cardiac Myosin Binding Protein-C Mutations in Families with Hypertrophic Cardiomyopathy. Circ. Cardiovasc. Genet. 2012;5:156–166. doi: 10.1161/CIRCGENETICS.111.960831. PubMed DOI

Seidman C.E., Seidman J. Identifying Sarcomere Gene Mutations in Hypertrophic Cardiomyopathy. Circ. Res. 2011;108:743–750. doi: 10.1161/CIRCRESAHA.110.223834. PubMed DOI PMC

Van Velzen H.G., Vriesendorp P.A., Oldenburg R.A., Van Slegtenhorst M.A., Van Der Velden J., Schinkel A.F., Michels M. Value of Genetic Testing for the Prediction of Long-Term Outcome in Patients with Hypertrophic Cardiomyopathy. Am. J. Cardiol. 2016;118:881–887. doi: 10.1016/j.amjcard.2016.06.038. PubMed DOI

Mathew J., Zahavich L., Lafreniere-Roula M., Wilson J., George K., Benson L., Bowdin S., Mital S. Utility of genetics for risk stratification in pediatric hypertrophic cardiomyopathy. Clin. Genet. 2017;93:310–319. doi: 10.1111/cge.13157. PubMed DOI

Lopes L.R., Brito D., Belo A., Cardim N. Genetic characterization and genotype-phenotype associations in a large cohort of patients with hypertrophic cardiomyopathy—An ancillary study of the Portuguese registry of hypertrophic cardiomyopathy. Int. J. Cardiol. 2018;278:173–179. doi: 10.1016/j.ijcard.2018.12.012. PubMed DOI

Ho C.Y., Day S.M., Ashley E.A., Michels M., Pereira A.C., Jacoby D., Cirino A.L., Fox J.C., Lakdawala N.K., Ware J., et al. Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy. Circulation. 2018;138:1387–1398. doi: 10.1161/CIRCULATIONAHA.117.033200. PubMed DOI PMC

Bonaventura J., Veselka J. Genetic testing in patients with hypertrophic cardiomyopathy. Vnitrni Lek. 2019;65:652–658. doi: 10.36290/vnl.2019.113. PubMed DOI

Ingles J., Doolan A., Chiu C.L., Seidman J., Seidman C., Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy: Implications for genetic testing and counselling. J. Med. Genet. 2005;42:e59. doi: 10.1136/jmg.2005.033886. PubMed DOI PMC

Blankenburg R., Hackert K., Wurster S., Deenen R., Seidman J., Seidman C.E., Lohse M.J., Schmitt J.P. β-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;115:227–237. doi: 10.1161/CIRCRESAHA.115.303178. PubMed DOI PMC

Dorn G.W., McNally E.M. Two Strikes and You’re Out. Circ. Res. 2014;115:208–210. doi: 10.1161/CIRCRESAHA.114.304383. PubMed DOI PMC

Whiffin N., Minikel E.V., Walsh R., O’Donnell-Luria A., Karczewski K., Ing A.Y., Barton P., Funke B., A Cook S., MacArthur D., et al. Using high-resolution variant frequencies to empower clinical genome interpretation. Genet. Med. 2017;19:1151–1158. doi: 10.1038/gim.2017.26. PubMed DOI PMC

Whiffin N., Walsh R., Govind R., Edwards M., Ahmad M., Zhang X., Tayal U., Buchan R., Midwinter W., E Wilk A., et al. CardioClassifier: Disease- and gene-specific computational decision support for clinical genome interpretation. Genet. Med. 2018;20:1246–1254. doi: 10.1038/gim.2017.258. PubMed DOI PMC

Baulina N.M., Kiselev I.S., Chumakova O.S., Favorova O.O. Hypertrophic Cardiomyopathy as an Oligogenic Disease: Transcriptomic Arguments. Mol. Biol. 2020;54:840–850. doi: 10.1134/S0026893320060023. PubMed DOI

Aurigemma G.P., de Simone G., Fitzgibbons T. Cardiac Remodeling in Obesity. Circ. Cardiovasc. Imaging. 2013;6:142–152. doi: 10.1161/CIRCIMAGING.111.964627. PubMed DOI

Robertson J., Lindgren M., Schaufelberger M., Adiels M., Björck L., Lundberg C.E., Sattar N., Rosengren A., Aberg M. Body Mass Index in Young Women and Risk of Cardiomyopathy. Circulation. 2020;141:520–529. doi: 10.1161/CIRCULATIONAHA.119.044056. PubMed DOI PMC

Fumagalli C., Maurizi N., Day S.M., Ashley E.A., Michels M., Colan S.D., Jacoby D., Marchionni N., Vincent-Tompkins J., Ho C.Y., et al. Association of Obesity With Adverse Long-term Outcomes in Hypertrophic Cardiomyopathy. JAMA Cardiol. 2020;5:65–68. doi: 10.1001/jamacardio.2019.4268. PubMed DOI PMC

Nollet E.E., Westenbrink B.D., de Boer R.A., Kuster D.W.D., van der Velden J. Unraveling the Genotype-Phenotype Relationship in Hypertrophic Cardiomyopathy: Obesity-Related Cardiac Defects as a Major Disease Modifier. J. Am. Heart Assoc. 2020;9:e018641. doi: 10.1161/JAHA.120.018641. PubMed DOI PMC

Tini G., Autore C., Musumeci B. The Many Faces of Arterial Hypertension in Hypertrophic Cardiomyopathy and Its Phenocopies: Bystander, Consequence, Modifier. High Blood Press. Cardiovasc. Prev. 2021;28:327–329. doi: 10.1007/s40292-021-00458-6. PubMed DOI

Siontis K.C., Ommen S.R., Geske J.B. Sex, Survival, and Cardiomyopathy: Differences Between Men and Women With Hypertrophic Cardiomyopathy. J. Am. Heart Assoc. 2019;8:e014448. doi: 10.1161/JAHA.119.014448. PubMed DOI PMC

Michels M., Soliman O.I., Phefferkorn J., Hoedemaekers Y.M., Kofflard M.J., Dooijes D., Majoor-Krakauer D., Cate F.J.T. Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers. Eur. Heart J. 2009;30:2593–2598. doi: 10.1093/eurheartj/ehp306. PubMed DOI

Lorenzini M., Norrish G., Field E., Ochoa J.P., Cicerchia M., Akhtar M.M., Syrris P., Lopes L.R., Kaski J.P., Elliott P.M. Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers. J. Am. Coll. Cardiol. 2020;76:550–559. doi: 10.1016/j.jacc.2020.06.011. PubMed DOI PMC

Geske J.B., Ong K.C., Siontis K.C., Hebl V.B., Ackerman M.J., O Hodge D., Miller V.M., A Nishimura R., Oh J.K., Schaff H., et al. Women with hypertrophic cardiomyopathy have worse survival. Eur. Heart J. 2017;38:3434–3440. doi: 10.1093/eurheartj/ehx527. PubMed DOI PMC

Veselka J., Faber L., Liebregts M., Cooper R., Kashtanov M., Hansen P.R., Bonaventura J., Polakova E., Hansvenclova E., Bundgaard H., et al. Sex-Related Differences in Outcomes of Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy. JACC Cardiovasc. Interv. 2021;14:1390–1392. doi: 10.1016/j.jcin.2021.03.066. PubMed DOI

Fumagalli C., Olivotto I. The Importance of Sex Differences in Patients With Hypertrophic Cardiomyopathy—Tailoring Management and Future Perspectives. Am. J. Med. Sci. 2020;360:433–434. doi: 10.1016/j.amjms.2020.07.004. PubMed DOI

Wang Y., Zhao H.-W., Wang C.-F., Meng Q.-K., Cui C.-S., Zhang X.-J., Zhu Y., Fan C.-Y., Luo D.-F., Chen B.-J., et al. Gender Disparities in Clinical Outcome After Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy in the Chinese Han Population: A Cohort Study. Heart Lung Circ. 2020;29:1856–1864. doi: 10.1016/j.hlc.2020.04.014. PubMed DOI

Meghji Z., Nguyen A., Fatima B., Geske J.B., Nishimura R.A., Ommen S.R., Lahr B.D., Dearani J.A., Schaff H.V. Survival Differences in Women and Men After Septal Myectomy for Obstructive Hypertrophic Cardiomyopathy. JAMA Cardiol. 2019;4:237–245. doi: 10.1001/jamacardio.2019.0084. PubMed DOI PMC

Rigopoulos A.G., Ali M., Abate E., Torky A.-R., Matiakis M., Mammadov M., Melnyk H., Vogt A., De Vecchis R., Bigalke B., et al. Advances in the diagnosis and treatment of transthyretin amyloidosis with cardiac involvement. Heart Fail. Rev. 2019;24:521–533. doi: 10.1007/s10741-019-09776-3. PubMed DOI

Maurer M.S., Schwartz J.H., Gundapaneni B., Elliott P., Merlini G., Waddington-Cruz M., Kristen A.V., Grogan M., Witteles R., Damy T., et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N. Engl. J. Med. 2018;379:1007–1016. doi: 10.1056/NEJMoa1805689. PubMed DOI

Chen Y.-J., Chien C.-S., Chiang C.-E., Chen C.-H., Cheng H.-M. From Genetic Mutations to Molecular Basis of Heart Failure Treatment: An Overview of the Mechanism and Implication of the Novel Modulators for Cardiac Myosin. Int. J. Mol. Sci. 2021;22:6617. doi: 10.3390/ijms22126617. PubMed DOI PMC

Prondzynski M., Mearini G., Carrier L. Gene therapy strategies in the treatment of hypertrophic cardiomyopathy. Pflügers Arch. Eur. J. Physiol. 2018;471:807–815. doi: 10.1007/s00424-018-2173-5. PubMed DOI

Fumagalli C., De Gregorio M.G., Zampieri M., Fedele E., Tomberli A., Chiriatti C., Marchi A., Olivotto I. Targeted Medical Therapies for Hypertrophic Cardiomyopathy. Curr. Cardiol. Rep. 2020;22:1–13. doi: 10.1007/s11886-020-1258-x. PubMed DOI

Sewanan L.R., Jacoby D.L. Novel Myosin-Based Therapies in Hypertrophic Cardiomyopathy. Curr. Treat. Options Cardiovasc. Med. 2021;23:1–12. doi: 10.1007/s11936-021-00921-6. DOI

Jiang J., Wakimoto H., Seidman J.G., Seidman C.E. Allele-Specific Silencing of MutantMyh6Transcripts in Mice Suppresses Hypertrophic Cardiomyopathy. Science. 2013;342:111–114. doi: 10.1126/science.1236921. PubMed DOI PMC

Cannon L., Yu Z.-Y., Marciniec T., Waardenberg A.J., Iismaa S.E., Nikolova-Krstevski V., Neist E., Ohanian M., Qiu M.R., Rainer S., et al. Irreversible Triggers for Hypertrophic Cardiomyopathy Are Established in the Early Postnatal Period. J. Am. Coll. Cardiol. 2015;65:560–569. doi: 10.1016/j.jacc.2014.10.069. PubMed DOI

Hsu P., Lander E.S., Zhang F. Development and Applications of CRISPR-Cas9 for Genome Engineering. Cell. 2014;157:1262–1278. doi: 10.1016/j.cell.2014.05.010. PubMed DOI PMC

Ma H., Marti-Gutierrez N., Park S.-W., Wu J., Lee Y., Suzuki K., Koski A., Jianhui G., Hayama T., Ahmed R., et al. Correction of a pathogenic gene mutation in human embryos. Nat. Cell Biol. 2017;548:413–419. doi: 10.1038/nature23305. PubMed DOI

Maron B.J. Clinical Course and Management of Hypertrophic Cardiomyopathy. N. Engl. J. Med. 2018;379:655–668. doi: 10.1056/NEJMra1710575. PubMed DOI

Ko C., Arscott P., Concannon M., Saberi S., Day S.M., Yashar B.M., Helms A. Genetic testing impacts the utility of prospective familial screening in hypertrophic cardiomyopathy through identification of a nonfamilial subgroup. Genet. Med. 2017;20:69–75. doi: 10.1038/gim.2017.79. PubMed DOI

Ingles J., Burns C., Bagnall R.D., Lam L., Yeates L., Sarina T., Puranik R., Briffa T., Atherton J.J., Driscoll T., et al. Nonfamilial Hypertrophic Cardiomyopathy. Circ. Cardiovasc. Genet. 2017;10 doi: 10.1161/CIRCGENETICS.116.001620. PubMed DOI

Bonaventura J., Norambuena P., Votýpka P., Hnátová H., Adlová R., Macek M., Veselka J., Jr M.M. Patients with hypertrophic obstructive cardiomyopathy after alcohol septal ablation have favorable long-term outcome irrespective of their genetic background. Cardiovasc. Diagn. Ther. 2020;10:193–200. doi: 10.21037/cdt.2020.01.12. PubMed DOI PMC

Gruner C., Ivanov J., Care M., Williams L., Moravsky G., Yang H., Laczay B., Siminovitch K., Woo A., Rakowski H. Toronto Hypertrophic Cardiomyopathy Genotype Score for Prediction of a Positive Genotype in Hypertrophic Cardiomyopathy. Circ. Cardiovasc. Genet. 2013;6:19–26. doi: 10.1161/CIRCGENETICS.112.963363. PubMed DOI

Liang L.W., Fifer M.A., Hasegawa K., Maurer M.S., Reilly M.P., Shimada Y.J. Prediction of Genotype Positivity in Patients with Hypertrophic Cardiomyopathy Using Machine Learning. Circ. Genom. Precis. Med. 2021;14 doi: 10.1161/CIRCGEN.120.003259. PubMed DOI PMC

Aziz A., Musiol S.K., Moody W.E., Pickup L., Cooper R., Lip G.Y.H. Clinical prediction of genotypes in hypertrophic cardiomyopathy: A systematic review. Eur. J. Clin. Investig. 2021:e13593. doi: 10.1111/eci.13593. PubMed DOI

Zhou H., Li L., Liu Z., Zhao K., Chen X., Lu M., Yin G., Song L., Zhao S., Zheng H., et al. Deep learning algorithm to improve hypertrophic cardiomyopathy mutation prediction using cardiac cine images. Eur. Radiol. 2020;31:3931–3940. doi: 10.1007/s00330-020-07454-9. PubMed DOI

Relationship Between Genotype Status and Clinical Outcome in Hypertrophic Cardiomyopathy