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Novel Missense Variant in MYL2 Gene Associated With Hypertrophic Cardiomyopathy Showing High Incidence of Restrictive Physiology

2020; Wolters Kluwer; Volume: 13; Issue: 2 Linguagem: Inglês

10.1161/circgen.119.002824

2574-8300

Marzia De Bortoli, Riccardo Vio, Cristina Basso, Martina Calore, Giovanni Minervini, Annalisa Angelini, Paola Melacini, Libero Vitiello, Giovanni Vazza, Gaetano Thiene, Silvio C. E. Tosatto, Domenico Corrado, Sabino Iliceto, Alessandra Rampazzo, Chiara Calore,

Galectins and Cancer Biology

HomeCirculation: Genomic and Precision MedicineVol. 13, No. 2Novel Missense Variant in MYL2 Gene Associated With Hypertrophic Cardiomyopathy Showing High Incidence of Restrictive Physiology Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBNovel Missense Variant in MYL2 Gene Associated With Hypertrophic Cardiomyopathy Showing High Incidence of Restrictive Physiology Marzia De Bortoli, PhD, Riccardo Vio, MD, Cristina Basso, MD, PhD, Martina Calore, PhD, Giovanni Minervini, PhD, Annalisa Angelini, MD, Paola Melacini, MD, Libero Vitiello, PhD, Giovanni Vazza, PhD, Gaetano Thiene, MD, Silvio Tosatto, PhD, Domenico Corrado, MD, PhD, Sabino Iliceto, MD, Alessandra Rampazzo, PhD and Chiara Calore, MD, PhD Marzia De BortoliMarzia De Bortoli Department of Biology (M.D.B., M.C., L.V., G.V., A.R.), University of Padua, Italy. Institute for Biomedicine, Eurac Research, Bolzano, Italy (M.D.B.). Affiliated Institute of the University of Lübeck, Germany (M.D.B.). , Riccardo VioRiccardo Vio Department of Cardiac, Thoracic, Vascular Sciences and Public Health (R.V., C.B., A.A., P.M., G.T., D.C., S.I., C.C.), University of Padua, Italy. , Cristina BassoCristina Basso https://orcid.org/0000-0002-0195-9753 Department of Cardiac, Thoracic, Vascular Sciences and Public Health (R.V., C.B., A.A., P.M., G.T., D.C., S.I., C.C.), University of Padua, Italy. , Martina CaloreMartina Calore Department of Biology (M.D.B., M.C., L.V., G.V., A.R.), University of Padua, Italy. IMAiA-Institute for Molecular Biology and RNA Technology, Faculty of Science and Engineering, Faculty of Health, Medicine and Life Sciences, Maastricht University, the Netherlands (M.C.). , Giovanni MinerviniGiovanni Minervini https://orcid.org/0000-0001-7013-5785 Department of Biomedical Sciences (G.M., S.T.), University of Padua, Italy. , Annalisa AngeliniAnnalisa Angelini Department of Cardiac, Thoracic, Vascular Sciences and Public Health (R.V., C.B., A.A., P.M., G.T., D.C., S.I., C.C.), University of Padua, Italy. , Paola MelaciniPaola Melacini Department of Cardiac, Thoracic, Vascular Sciences and Public Health (R.V., C.B., A.A., P.M., G.T., D.C., S.I., C.C.), University of Padua, Italy. , Libero VitielloLibero Vitiello Department of Biology (M.D.B., M.C., L.V., G.V., A.R.), University of Padua, Italy. Interuniversity Institute of Myology, Italy (L.V.). , Giovanni VazzaGiovanni Vazza Department of Biology (M.D.B., M.C., L.V., G.V., A.R.), University of Padua, Italy. , Gaetano ThieneGaetano Thiene Department of Cardiac, Thoracic, Vascular Sciences and Public Health (R.V., C.B., A.A., P.M., G.T., D.C., S.I., C.C.), University of Padua, Italy. , Silvio TosattoSilvio Tosatto Department of Biomedical Sciences (G.M., S.T.), University of Padua, Italy. , Domenico CorradoDomenico Corrado https://orcid.org/0000-0003-1487-0392 Department of Cardiac, Thoracic, Vascular Sciences and Public Health (R.V., C.B., A.A., P.M., G.T., D.C., S.I., C.C.), University of Padua, Italy. , Sabino IlicetoSabino Iliceto Department of Cardiac, Thoracic, Vascular Sciences and Public Health (R.V., C.B., A.A., P.M., G.T., D.C., S.I., C.C.), University of Padua, Italy. , Alessandra RampazzoAlessandra Rampazzo Correspondence to: Alessandra Rampazzo, PhD, Department of Biology, University of Padua, Via G. Colombo 3, 35131 Padua, Italy. Email E-mail Address: [email protected] https://orcid.org/0000-0003-3884-8843 Department of Biology (M.D.B., M.C., L.V., G.V., A.R.), University of Padua, Italy. CRIBI Biotechnology Centre (A.R.), University of Padua, Italy. and Chiara CaloreChiara Calore Department of Cardiac, Thoracic, Vascular Sciences and Public Health (R.V., C.B., A.A., P.M., G.T., D.C., S.I., C.C.), University of Padua, Italy. Originally published31 Jan 2020https://doi.org/10.1161/CIRCGEN.119.002824Circulation: Genomic and Precision Medicine. 2020;13:e002824Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 31, 2020: Ahead of Print Hypertrophic cardiomyopathy (HCM) is the most frequent inherited cardiac disease, and its prognosis can be severely worsened by the presence of restrictive filling pattern and atrial fibrillation (AF).1,2 Here, we report a novel, highly penetrant MYL2 variant in a multigenerational HCM family showing high incidence of restrictive filling pattern and AF.Genetic testing was performed in affected subject IV-5 (Figure [A]), using a next-generation sequencing panel of 56 genes previously associated with inherited cardiomyopathies. Four different variants have been identified: c.496G>C p.D166H in MYL2 gene; c.83C>T p.A28V in TNNT2 gene; c.1718C>T p.S573L in LMNA gene; and c.2611C>T p.R871C in MYH6 gene. Moreover, a rare missense variant (c.5279C>T; p.T1760M) in MYH7 gene was identified in subjects III-4; III-7; III-17; IV-11; and IV-13. Importantly, the MYL2 variant had not been previously reported in the gnomAD database, whereas all the other variants were already present with a minor allele frequency ≤0.1%. Prediction tools and conservation scores indicated that MYL2, MYH7, and MYH6 variants could be damaging, while TNNT2 and LMNA variants could be benign. On the basis of American College of Medical Genetics and Genomics guidelines, we classified the LMNA variant as likely benign, the MYH7, TNNT2, and MYH6 variants as uncertain significance and the MYL2 variant as likely pathogenic. Specifically, the MYL2 variant affects the last and highly conserved amino acid of the protein, which lies at a critical region of the regulatory light chain that makes contact with the bent structure of the myosin lever arm. In silico structural analyses suggested that p.D166H may lead to an altered lever arm steric conformation during the cross-bridge cycle (Figure [B]), as already hypothesized for the p.D166V variant previously associated with malignant HCM phenotype.3Download figureDownload PowerPointFigure. Novel missense variant in MYL2 gene and hypertrophic cardiomyopathy.A, Pedigree of the family. B, Cartoon representation of the human β-cardiac myosin interacting heads motif (IHM) 3-dimensional structure (PDBid: 5TBY). Myosin heads are represented in light and dark blue, respectively. MYL3 acting as an essential stabilizing light chain is represented with green nuances while the regulatory MYL2 chains are in red and yellow. Zoomed: overview of the myosin heavy chain/MYL2 interaction interface. Residues at the interface are visualized as sticks, with dotted lines highlighting electrostatic interactions. C, ECG of subject III-25 showing first degree AV block and left anterior hemiblock (before pacemaker implantation). D, Four chambers echocardiographic view of subject III-25 showing biatrial enlargement and septal hypertrophy (before pacemaker implantation). E, Gross view of the left cardiac chambers of subject III-25: note the severe dilatation of the left atrium with an almost preserved left ventricular volume. The thickness of the left ventricular (LV) free wall and ventricular septum is 13 and 14 mm, respectively, in keeping with symmetrical mild hypertrophy. F, Histology of the LV free wall of subject III-25: note the diffuse disarray of the cardiac myocytes with tiny interstitial fibrosis (trichrome stain). G, Demographic and clinical characteristics of MYL2 carriers. H, Echocardiographic findings of MYL2 carriers.The novel MYL2 missense variant was identified in 12 additional family members (Figure [A]); 11 of them had been diagnosed with HCM and one (a 26-years-old woman, IV-2) showed a borderline phenotype (maximal left ventricular wall thickness =12 mm). This familial segregation yielded a logarithm of the odds score of 5.35 at a recombination fraction =0.00 (disease allele frequency of 1/500 and penetrance of 0.9), thus strongly supporting the association between the MYL2 variant and the HCM phenotype.The proband (subject III-7) is a 76-year-old woman diagnosed with HCM at the age of 31. She experienced paroxysmal AF complicated with acute decompensated heart failure. Sinus rhythm was temporarily obtained by electrical cardioversions, but after a relapse, the AF became permanent and symptoms worsened (New York Heart Association class III). The proband's brother (subject III-4) was diagnosed when he was 20-years-old. At the age of 55, he evolved toward the end-stage phase, worsened by AF onset. He was implanted with a cardioverter-defibrillator for primary prevention, and 3 years later, the device appropriately interrupted ventricular fibrillation. His clinical course progressively evolved toward left ventricular dilation with severe impairment of systolic function (ejection fraction =24%) and development of refractory heart failure; he eventually died at the age of 66.Four other patients harboring the MYL2 variant also experienced a particularly adverse clinical outcome. Subject III-25 (Figure [C–F]) was a female diagnosed with HCM at the age of 26, with exertional dyspnea and angina, who underwent pacemaker implantation for complete atrioventricular block and thereafter progressed toward congestive heart failure; she died at 54. Subject IV-8 showed a restrictive HCM with mild hypertrophy since the time of diagnosis at 15-years-old, with preserved ejection fraction, and severe atrial enlargement. He had become symptomatic for dyspnea and palpitation since his early adolescence and developed paroxysmal AF at the age of 17 with subsequent episodes of pulmonary embolism in the context of right atrial thrombi, which represent a very unusual echocardiographic finding. Heart failure symptoms had rapidly become severe (New York Heart Association class III–IV), requiring cardiac transplantation at the age of 20; unfortunately, he succumbed 16 days after surgery to malignant pulmonary hypertension. Patient III-1 was diagnosed with HCM at the age of 51, and after 10 years, he underwent implanted with a cardioverter-defibrillator implantation for symptomatic bradycardia and high risk of arrhythmic events. He became progressively symptomatic with frequent hospitalizations for recurring heart failure in the presence of restrictive HCM with preserved ejection fraction and AF; he died of refractory heart failure at age 72. Patient III-15 was diagnosed when she was 44 and died at age 66 of embolic stroke.The restrictive phenotype (eg, no or minimal left ventricular hypertrophy—maximal left ventricular wall thickness ≤15 mm—and severe diastolic dysfunction) that we describe in subject IV-8 had been reported by Kubo et al4 in 19 (1.5%) out of 1226 affected individuals from 688 families. Compared with other patients with HCM, those with the restrictive phenotype showed a higher prevalence of AF, New York Heart Association functional class III/IV, greater left atrial diameters, and lower magnitude of maximal left ventricle wall thickness while no one had left ventricular outflow tract obstruction.Within the family reported here, 62% of MYL2 carriers experienced AF (Figure [G]); this value is three times higher than that found in the general HCM population1 and could be linked to the severe diastolic dysfunction present in this family (Figure [H]). Specifically, 38% of MYL2 carriers in the kindred we are describing, showed a restrictive filling pattern, much higher than what had previously been reported.4 Other parameters linked to AF are age, atrial enlargement, and fibrosis of the atrial myocardium, the latter of which may represent the substrate for reentry. In particular, left atrial diameter is a strong predictor for AF and stroke in patients with HCM, and when ≥45 mm it should trigger further investigations to detect AF.5 Among the subjects displaying the MYL2 variant in this family, we found a mean left atrial anteroposterior diameter of 45±12 at baseline, which further increased to 54±14 mm during follow-up.In conclusion, the novel MYL2 variant that we described here is associated with high incidence of restrictive physiology, AF, and poor clinical outcomes. Of course, given that all affected individuals belong to the same family, one could not rule out the possibility that other shared genetic—and environmental—factors might also contribute to their cardiac phenotype. Further multicentric studies will be needed to thoroughly assess the impact of MYL2 variants on HCM prognosis.Sources of FundingThis study was funded by the University of Padua Research Project (PRAT) CPDA133979; the TRANSAC Strategic Research Grant CPDA133979/13, University of Padua, Italy; Registry for Cardio-Cerebro-Vascular Pathology, Veneto Region, Venice, Italy.DisclosuresNone.Footnotes*Drs De Bortoli and Vio contributed equally to this work.For Sources of Funding and Disclosures, see page 97.Correspondence to: Alessandra Rampazzo, PhD, Department of Biology, University of Padua, Via G. Colombo 3, 35131 Padua, Italy. Email alessandra.[email protected]itReferences1. Rowin EJ, Hausvater A, Link MS, Abt P, Gionfriddo W, Wang W, Rastegar H, Estes NAM, Maron MS, Maron BJ. Clinical profile and consequences of atrial fibrillation in hypertrophic cardiomyopathy.Circulation. 2017; 136:2420–2436. doi: 10.1161/CIRCULATIONAHA.117.029267LinkGoogle Scholar2. Angelini A, Calzolari V, Thiene G, Boffa GM, Valente M, Daliento L, Basso C, Calabrese F, Razzolini R, Livi U, et al. Morphologic spectrum of primary restrictive cardiomyopathy.Am J Cardiol. 1997; 80:1046–1050. doi: 10.1016/s0002-9149(97)00601-2CrossrefMedlineGoogle Scholar3. Muthu P, Liang J, Schmidt W, Moore JR, Szczesna-Cordary D. In vitro rescue study of a malignant familial hypertrophic cardiomyopathy phenotype by pseudo-phosphorylation of myosin regulatory light chain.Arch Biochem Biophys. 2014; 552–553:29–39. doi: 10.1016/j.abb.2013.12.011CrossrefMedlineGoogle Scholar4. Kubo T, Gimeno JR, Bahl A, Steffensen U, Steffensen M, Osman E, Thaman R, Mogensen J, Elliott PM, Doi Y, et al. Prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy with restrictive phenotype.J Am Coll Cardiol. 2007; 49:2419–2426. doi: 10.1016/j.jacc.2007.02.061CrossrefMedlineGoogle Scholar5. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, 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.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Kazmierczak K, Liang J, Gomez-Guevara M and Szczesna-Cordary D (2022) Functional comparison of phosphomimetic S15D and T160D mutants of myosin regulatory light chain exchanged in cardiac muscle preparations of HCM and WT mice, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2022.988066, 9 Vriz O, AlSergani H, Elshaer A, Shaik A, Mushtaq A, Lioncino M, Alamro B, Monda E, Caiazza M, Mauro C, Bossone E, Al-Hassnan Z, Albert-Brotons D and Limongelli G (2021) A complex unit for a complex disease: the HCM-Family Unit, Monaldi Archives for Chest Disease, 10.4081/monaldi.2021.2147 Vio R, Angelini A, Basso C, Cipriani A, Zorzi A, Melacini P, Thiene G, Rampazzo A, Corrado D and Calore C (2021) Hypertrophic Cardiomyopathy and Primary Restrictive Cardiomyopathy: Similarities, Differences and Phenocopies, Journal of Clinical Medicine, 10.3390/jcm10091954, 10:9, (1954) April 2020Vol 13, Issue 2 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.119.002824PMID: 32004434 Originally publishedJanuary 31, 2020 Keywordsdiseaseatrial fibrillationprognosisgenescardiomyopathiesPDF download Advertisement SubjectsCardiomyopathyGeneticsSudden Cardiac Death