Enrichment of Rare Variants in Loeys–Dietz Syndrome Genes in Spontaneous Coronary Artery Dissection but Not in Severe Fibromuscular Dysplasia
2020; Lippincott Williams & Wilkins; Volume: 142; Issue: 10 Linguagem: Inglês
10.1161/circulationaha.120.045946
ISSN1524-4539
AutoresAline Verstraeten, Melanie Perik, Anna Baranowska, Josephina Meester, Lotte Van Den Heuvel, Jarl Bastianen, Marlies Kempers, Ingrid P.C. Krapels, Angela H.E.M. Maas, Andrea L. Rideout, Anthony Vandersteen, Glenda Sobey, Diana Johnson, Erik Fransén, Neeti Ghali, Tom R. Webb, Abtehale Al-Hussaini, Peter de Leeuw, P. Delmotte, Marilucy Lopez‐Sublet, Marco Pappaccogli, Muriel Sprynger, Laurent Toubiana, Lut Van Laer, Fleur S. van Dijk, Miikka Vikkula, Nilesh J. Samani, Alexandre Persu, David Adlam, Bart Loeys, Christophe Beauloye, Patrick Chenu, Frank Hammer, Pierre Goffette, Parla Astarci, André Peeters, Robert Verhelst, Patricia Van der Niepen, Frank Van Tussenbroek, Tine De Backer, Sofie Gevaert, Dimitri Hemelsoet, Luc Defreyne, Hilde Heuten, Laetitia Yperzeele, Thijs van der Zijden, Jean‐Philippe Lengelé, Jean-Marie Krzesinski, Peter Verhamme, Thomas Vanassche, Pasquale Scoppettuolo, Jean-Claude Wautrecht, Bojan Jelaković, Živka Dika, Rosa María Bruno, Stefano Taddei, Caterina Romanini, Ilaria Petrucci, Franco Rabbia, Silvia Di Monaco, Gian Paolo Rossi, Silvia Lerco, Pietro Minuz, Giancarlo Mansueto, Sergio De Marchi, Denise Marcon, Bram Kroon, Wilko Spiering, Bert‐Jan H. van den Born, Esteban Poch, Enrique Montagud‐Marrahí, Alícia Molina‐Andújar, Elena Guillén, Marta Burrel, Gregor Wuerzner, Lucia Mazzolai, Giacomo Buso,
Tópico(s)Pulmonary Hypertension Research and Treatments
ResumoHomeCirculationVol. 142, No. 10Enrichment of Rare Variants in Loeys–Dietz Syndrome Genes in Spontaneous Coronary Artery Dissection but Not in Severe Fibromuscular Dysplasia Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialOpen AccessLetterPDF/EPUBEnrichment of Rare Variants in Loeys–Dietz Syndrome Genes in Spontaneous Coronary Artery Dissection but Not in Severe Fibromuscular Dysplasia Aline Verstraeten, PhD, Melanie H.A.M. Perik, MSc, Anna A. Baranowska, MSc, Josephina A.N. Meester, PhD, Lotte Van Den Heuvel, MSc, Jarl Bastianen, MSc, Marlies Kempers, MD, PhD, Ingrid P.C. Krapels, MD, PhD, Angela Maas, MD, PhD, Andrea Rideout, MSc, Anthony Vandersteen, MD, PhD, Glenda Sobey, MD, Diana Johnson, MSc, Erik Fransen, PhD, Neeti Ghali, MD, Tom Webb, PhD, Abtehale Al-Hussaini, MBBS, Peter de Leeuw, MD, PhD, Philippe Delmotte, MD, Marilucy Lopez-Sublet, MD, Marco Pappaccogli, MD, Muriel Sprynger, MD, Laurent Toubiana, PhD, European/International Fibromuscular Dysplasia Registry and Initiative (FEIRI) Lut Van Laer, PhD, Fleur S. Van Dijk, MD, PhD, Miikka Vikkula, MD, PhD, Nilesh J. Samani, MD, Alexandre Persu, MD, PhD, David Adlam, DPhil and Bart Loeys, MD, PhD Aline VerstraetenAline Verstraeten https://orcid.org/0000-0002-4007-9695 Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Belgium (A. Verstraeten, M.H.A.M.P., J.A.N.M., L.V.D.H., J.B., E.F., L.V.L., B.L.). , Melanie H.A.M. PerikMelanie H.A.M. Perik Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Belgium (A. Verstraeten, M.H.A.M.P., J.A.N.M., L.V.D.H., J.B., E.F., L.V.L., B.L.). , Anna A. BaranowskaAnna A. Baranowska https://orcid.org/0000-0003-0827-6792 Department of Cardiovascular Sciences and National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (A.A.B., T.W., A.A.-H., N.J.S., D.A.). , Josephina A.N. MeesterJosephina A.N. Meester Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Belgium (A. Verstraeten, M.H.A.M.P., J.A.N.M., L.V.D.H., J.B., E.F., L.V.L., B.L.). , Lotte Van Den HeuvelLotte Van Den Heuvel Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Belgium (A. Verstraeten, M.H.A.M.P., J.A.N.M., L.V.D.H., J.B., E.F., L.V.L., B.L.). , Jarl BastianenJarl Bastianen Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Belgium (A. Verstraeten, M.H.A.M.P., J.A.N.M., L.V.D.H., J.B., E.F., L.V.L., B.L.). , Marlies KempersMarlies Kempers Department of Human Genetics (M.K., B.L.), Radboud University Nijmegen Medical Center, The Netherlands. , Ingrid P.C. KrapelsIngrid P.C. Krapels Department of Clinical Genetics (I.P.C.K.), Maastricht University Medical Centre, The Netherlands. , Angela MaasAngela Maas Department of Cardiology (A.M.), Radboud University Nijmegen Medical Center, The Netherlands. , Andrea RideoutAndrea Rideout Maritime Medical Genetics Service, Izaak Walton Killam (IWK) Health Centre, Halifax, Canada (A.R., A. Vandersteen). , Anthony VandersteenAnthony Vandersteen Maritime Medical Genetics Service, Izaak Walton Killam (IWK) Health Centre, Halifax, Canada (A.R., A. Vandersteen). Division of Medical Genetics, Department of Pediatrics, Dalhousie University, Halifax, Canada (A. Vandersteen). , Glenda SobeyGlenda Sobey Ehlers Danlos Syndrome National Diagnostic Service, Sheffield Clinical Genetics Department, Northern General Hospital, United Kingdom (G.S., D.J.). , Diana JohnsonDiana Johnson Ehlers Danlos Syndrome National Diagnostic Service, Sheffield Clinical Genetics Department, Northern General Hospital, United Kingdom (G.S., D.J.). , Erik FransenErik Fransen Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Belgium (A. Verstraeten, M.H.A.M.P., J.A.N.M., L.V.D.H., J.B., E.F., L.V.L., B.L.). StatUa Center for Statistics, University of Antwerp, Belgium (E.F.). , Neeti GhaliNeeti Ghali https://orcid.org/0000-0003-2847-1376 Ehlers-Danlos Syndrome, National Diagnostic Service, Northwick Park and St. Mark's Hospitals, Harrow, United Kingdom (N.G., F.S.V.D.). , Tom WebbTom Webb https://orcid.org/0000-0001-5998-8226 Department of Cardiovascular Sciences and National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (A.A.B., T.W., A.A.-H., N.J.S., D.A.). , Abtehale Al-HussainiAbtehale Al-Hussaini Department of Cardiovascular Sciences and National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (A.A.B., T.W., A.A.-H., N.J.S., D.A.). , Peter de LeeuwPeter de Leeuw https://orcid.org/0000-0002-4949-5812 Department of Medicine (P.D.L.), Maastricht University Medical Centre, The Netherlands. , Philippe DelmottePhilippe Delmotte Division of Cardiology, Centre Hospitalier Universitaire Ambroise Paré, Mons, Belgium (P.D.). , Marilucy Lopez-SubletMarilucy Lopez-Sublet Department of Internal Medicine, European Society of Hypertension Excellence Centre, Centre Hospitalier Universitaire (CHU) Avicenne, assistance publique hôpitaux de paris (AP-HP), Bobigny, France (M.L.-S.). , Marco PappaccogliMarco Pappaccogli https://orcid.org/0000-0003-4107-8122 Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Division of Cardiology, Cliniques Universitaires Saint-Luc (M.P., A.P.), Université Catholique de Louvain, Brussels, Belgium. Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Turin, Italy (M.P.). , Muriel SpryngerMuriel Sprynger https://orcid.org/0000-0003-4358-0183 Cardiology Department, University of Liège Hospital, Belgium (M.S.). , Laurent ToubianaLaurent Toubiana Sorbonne Université, Université Paris 13, Sorbonne Paris Cité, Institut national de la santé et de la recherche médicale (INSERM), UMR_S 1142, Laboratoire d'Informatique Médicale et d'Ingénieurie des Connaissances en e-Santé (LIMICS), Institut de recherche pour la valorisation des données de santé (IRSAN), France (L.T.). , European/International Fibromuscular Dysplasia Registry and Initiative (FEIRI) , Lut Van LaerLut Van Laer Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Belgium (A. Verstraeten, M.H.A.M.P., J.A.N.M., L.V.D.H., J.B., E.F., L.V.L., B.L.). , Fleur S. Van DijkFleur S. Van Dijk Ehlers-Danlos Syndrome, National Diagnostic Service, Northwick Park and St. Mark's Hospitals, Harrow, United Kingdom (N.G., F.S.V.D.). , Miikka VikkulaMiikka Vikkula https://orcid.org/0000-0002-6236-338X Human Molecular Genetics, de Duve Institute (M.V.), Université Catholique de Louvain, Brussels, Belgium. , Nilesh J. SamaniNilesh J. Samani Department of Cardiovascular Sciences and National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (A.A.B., T.W., A.A.-H., N.J.S., D.A.). , Alexandre PersuAlexandre Persu https://orcid.org/0000-0002-4007-9695 Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Division of Cardiology, Cliniques Universitaires Saint-Luc (M.P., A.P.), Université Catholique de Louvain, Brussels, Belgium. , David AdlamDavid Adlam David Adlam, MD, PhD, Department of Cardiovascular Sciences, NIHR Leicester Biomedical Research Centre, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, United Kingdom. Email E-mail Address: [email protected] https://orcid.org/0000-0002-0080-9884 Department of Cardiovascular Sciences and National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (A.A.B., T.W., A.A.-H., N.J.S., D.A.). and Bart LoeysBart Loeys Correspondence to Bart Loeys, MD, PhD, Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital Prins Boudewijnlaan 43, 2650 Antwerp, Belgium; Email E-mail Address: [email protected] https://orcid.org/0000-0003-3703-9518 Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Belgium (A. Verstraeten, M.H.A.M.P., J.A.N.M., L.V.D.H., J.B., E.F., L.V.L., B.L.). Department of Human Genetics (M.K., B.L.), Radboud University Nijmegen Medical Center, The Netherlands. and Collaborators of the European/International Fibromuscular Dysplasia Registry and Initiative (FEIRI) Originally published8 Sep 2020https://doi.org/10.1161/CIRCULATIONAHA.120.045946Circulation. 2020;142:1021–1024Spontaneous coronary artery dissection (SCAD) is a prime cause of acute myocardial infarction in women < 50 years. Fibromuscular dysplasia (FMD) is present in 17% to 86% of patients with SCAD.1 In contrast, the prevalence of SCAD in FMD cohorts is <3%.1 Although the association between these 2 conditions has gained significant interest over the past years, the convergent underlying molecular mechanisms remain elusive.Familial recurrence studies pointed to a genetic contribution for SCAD and FMD.2 In case reports and a small-scale exome sequencing-based cohort study, SCAD has occasionally been linked to FBN1, COL3A1, and SMAD3 mutations.2 For FMD, a low yield of molecular testing for syndromic thoracic aortic aneurysm and dissection genes has been reported.2,3 We aimed to investigate the contribution of rare genetic variants in 25 known thoracic aortic aneurysm and dissection genes to the cause of SCAD and FMD because of the frequent association between the 2 entities. Haloplex-based gene panel sequencing was performed in a large multicenter unrelated patient cohort comprising 179 patients with SCAD±FMD and 102 patients with severe FMD only. The study has full United Kingdom Health Research Authority ethical clearance, and Institutional Review Board approval was obtained from the University of Antwerp and Université Catholique de Louvain. All patients signed informed consent. Variant filtering involved selection of heterozygous nonsynonymous coding or splice site (±2bp and +5bp) variants that are absent in gnomAD v2.1.1, have a minor allele frequency 20. After Sanger sequencing validation, selected variants were classified according to the American College of Medical Genetics guidelines. As an independent "control" cohort, gnomAD (genome aggregation database) v2.1.1 (approximately representing the general population) was filtered identically.4 Two case–control burden analyses were subsequently performed using Fisher exact (expected values <5) or chi-square statistics (expected values ≥5): SCAD±FMD versus gnomAD and FMD only versus gnomAD. To address the multiple testing burden, the significance of the association tests was evaluated using false discovery rate analysis by means of the q-value method. A q value G (p.Pro207Ala)0VUS (PP2; PM2)FNYCx/RCA………SMAD2 c.1082A>C (p.Asn361Thr)0LP (PP2-3; PM1-2)MYYLAD…Tortuosity carotid/iliac artery…SMAD2 c.1108C>T (p.Pro370Ser)0LP (PP2-3; PM1-2)FNNRCAR/CC/otherArterial dissection…SMAD3 c.871+1G>A0LP (PP3; PM1-2,4)FYNLAD…Infrarenal aneurysmSister: incidentally identified small brain aneurysm (–)Brother: splenic aneurysm requiring surgery (+)Mother: abdominal aortic rupture (?)TGFB2 c.440C>T (p.Pro147Leu)4.1E-4VUS (PM1)FNYLADR……TGFB2 c.440C>T (p.Pro147Leu)4.1E-4VUS (PM1)FNNLAD………TGFB2 c.631C>T (p.Arg211Cys)3.2E-5VUS (PP3; PM1)FNNLADR/CCVertebral artery dissection…TGFB2 c.740G>T (p.Gly247Val)0VUS (PP3; PM1-2)FNNLAD………TGFB3 c.454C>T (p.Arg152Trp)1.4E-5VUS (PP3; PM1)FYNLADRCommon iliac artery aneurysm…TGFB3 c.463C>T (p.Arg155Trp)0VUS (PP3; PM1-2)FYNOM2…Tortuosity vertebral arteries…TGFB3 c.813G>C (p.Lys271Asn)7.4E-5VUS (PM1)F?YCx?…Brother: thoracic aortic aneurysm (?)TGFB3 c.1202T>C (p.Leu401Pro)0LP (PP3,5; PM1-2)FNN…NA…Father: abdominal and thoracic aortic aneurysm (+)TGFBR1 c.739G>A (p.Glu247Lys)0VUS (PP3; PM1-2)MNNLAD………TGFBR1 c.1499G>C (p.Gly500Ala)4.0E-6VUS (-)FNYLADR/CCArterial dissection…TGFBR2 c.1082A>G (p.Tyr361Cys)0VUS (PP3; PM1-2)FNYNA…CC aneurysm and arterial dissection…TGFBR2 c.1718C>T (p.Ser573Leu)1.6E-5VUS (PP3)FNNRDPR……TGFBR2 c.1396+5G>T0LP (PP3; PM2,4,6)FYNCx……(de novo)LOX c.893T>G (p.Met298Arg)0P (PP3; PM1-2; PS1,3)FYYCxR…Mother: brain aneurysm (?)FLNA c.3806G>A (p.Gly1269Asp)0LP (PP2-3; PM2,4)FNYLAD…Mild aortic dilationMother: thoracic aortic aneurysm and rupture (?)Daughter: BAV with mild ascending aortic aneurysm (?)COL3A1 c.737delG (p.Gly246Aspfs*17)0P (PP3; PM2; PVS1)FN?…RArterial aneurysm…COL3A1 c.2177G>T (p.Gly726Val)0LP (PP2-3; PM1-2,5)FNYLAD/Cx………Extracoronary arterial involvement includes tortuosity, aneurysm, or dissection of noncoronary arteries. Family history is deemed positive on documentation of at least 1 first- or second-degree relative with SCAD, FMD, or arterial aneurysm/dissection. ? indicates unknown variant status; (–), variant is absent; (+), variant is present; ACMG, American College of Medical Genetics; BAV, bicuspid aortic valve; CC, cervico-cephalic; CTD, connective tissue disease findings; Cx, circumflex coronary artery; F, female; FMD, fibromuscular dysplasia; gnomAD, genome aggregation database; HT, hypertension; LAD, left anterior descending coronary artery; LDS, Loeys–Dietz syndrome; LP, likely pathogenic; M, male; MAF, minor allele frequency; N, no; NA, yes, but the location is unknown; OM2, obtuse marginal 2; P, pathogenic; R, renal; RCA, right coronary artery; RDP, right descending posterior coronary artery; SCAD, spontaneous coronary artery dissection; TAAD, thoracic aortic aneurysm and dissection; VUS, variant of uncertain significance; and Y, yes.Despite previous identification of elevated TGFB1 and TGFB2 plasma levels in patients with mostly severe FMD,2 neither the single-gene analyses nor combined LDS gene analysis (1/204 [0.5%] versus 3485/235 972 [1.5%]; P=3.8E-1) yielded significant P values in our FMD-only series. However, we did identify 1 multifocal FMD patient with a TGFB3 variant (p.Leu401Pro) that was previously reported in LDS,5 and for the first time identified a patient with FMD (multifocal) with a pathogenic COL3A1 variant (p.Gly246Aspfs*17).In conclusion, we demonstrated that rare variants in the known LDS genes impinge on SCAD risk, implying a pathophysiological role for dysregulated transforming growth factor β signaling and, hence, opening new avenues for SCAD research and future prevention and therapy. Although validation in other SCAD cohorts is warranted, our results advocate for routine molecular diagnostic screening of LDS genes in patients with SCAD, even in those without connective tissue disease manifestations. We showed that pathogenic FLNA and LOX variants are occasionally found in SCAD±FMD cases and revealed the presence of pathogenic COL3A1 variants in both patients with SCAD±FMD and patients with FMD only.Gene panel sequencing was done for ACTA2, BGN, COL3A1, ELN, EMILIN1, FBN1/2, FLNA, FOXE3, LOX, MAT2A, MFAP5, MYH11, MYLK, NOTCH1, PRKG1, SKI, SMAD2/3/4/6, TGFB2/3,and TGFBR1/2. For all samples, at least 99% of the target region was covered at ≥30×. The following transcripts were used to annotate all variants in the associated genes or (likely) pathogenic variants in any of the other genes: ENST00000402690, ENST00000327367, ENST00000366929, ENST00000238682, ENST00000374994, ENST00000359013, ENST00000304636, ENST00000369850, and ENST00000231004.AcknowledgmentsWe are grateful for the support of SCAD and FMD survivors. We thank our clinical colleagues who have referred SCAD and FMD cases to our research study. In the United Kingdom we specifically acknowledge the support of Alice Wood, Ellie Clarke, Jenny Middleton, Jane Plume, and Donna Alexander for all their support in the SCAD research. We acknowledge the leadership of the European Society of Cardiology - Acute Cardiovascular Care Association (ESC-ACCA) SCAD Study Group. In addition, we thank Ulrike Schwarze for her contribution to the molecular part of this study. We acknowledge the VASCERN (European Reference Network on Rare Vascular Disorders). Drs Loeys and Verstraeten are members of the VASCERN Heritable Thoracic Aortic Diseases (HTAD) and Medium Sized Arteries (MSA) working groups. Dr Vikkula is a member of the Vascular Anomalies (VASCA) working group.Sources of FundingThis research was supported by funding from the University of Antwerp (GOA, Methusalem-OEC grant "Genomed" FFB190208), the Research Foundation - Flanders (G.0356.17), the Dutch Heart Foundation (2013T093), the Marfan Foundation, the Fonds de la Recherche Scientifique (T.0026.14), BeatSCAD, the British Heart Foundation (PG/13/96/30608), the National Institute of Health Research Rare Disease Translational Collaboration, and the Leicester National Institute of Health Research Biomedical Research Center. Dr Loeys is a senior clinical investigator of the Research Foundation - Flanders and holds a consolidator grant from the European Research Council (Genomia - ERC-COG-2017-771945). Drs Verstraeten and Meester hold postdoctoral fellowships of the Research Foundation - Flanders, and Ms Van Den Heuvel is supported by a Research Foundation - Flanders PhD scholarship.DisclosuresDr Adlam has received research funding from Abbott Vascular Inc to support a clinical research fellow. He has also received funding and support from Astra Zeneca Inc for genetics research into SCAD. He has undertaken unrelated consultancy for GE Inc. The other authors report no conflicts.AppendixCollaborators of the European/International Fibromuscular Dysplasia Registry and Initiative (FEIRI)Alexandre Persu, Marco Pappaccogli, Christophe Beauloye, Patrick Chenu, Frank Hammer, Pierre Goffette, Parla Astarci, André Peeters, Robert Verhelst, Miikka Vikkula, Patricia Van der Niepen, Frank Van Tussenbroek, Tine De Backer, Sofie Gevaert, Dimitri Hemelsoet, Luc Defreyne, Hilde Heuten, Laetitia Yperzeele, Thijs Van der Zijden, Jean-Philippe Lengelé, Jean-Marie Krzesinski, Muriel Sprynger, Philippe Delmotte, Peter Verhamme, Thomas Vanassche, Pasquale Scoppettuolo, Jean-Claude Wautrecht, Bojan Jelaković, Zivka Dika, Rosa Maria Bruno, Stefano Taddei, Caterina Romanini, Ilaria Petrucci, Franco Rabbia, Marco Pappaccogli, Silvia Di Monaco, Gian Paolo Rossi, Silvia Lerco, Pietro Minuz, Giancarlo Mansueto, Sergio De Marchi, Denise Marcon, Bram Kroon, Peter de Leeuw, Wilko Spiering, Bert-Jan van den Born, Esteban Poch, Enrique Montagud-Marrahi, Alicia Molina, Elena Guillen, Marta Burrel, Gregor Wuerzner, Lucia Mazzolai, Giacomo BusoFootnotes*Drs Persu, Adlam, and Loeys contributed equally.https://www.ahajournals.org/journal/circData sharing: The data that support the findings of this study are available from the corresponding author upon reasonable request.The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.120.045946.Correspondence to Bart Loeys, MD, PhD, Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital Prins Boudewijnlaan 43, 2650 Antwerp, Belgium; Email bart.[email protected]beDavid Adlam, MD, PhD, Department of Cardiovascular Sciences, NIHR Leicester Biomedical Research Centre, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, United Kingdom. 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Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.https://doi.org/10.1161/CIRCULATIONAHA.120.045946PMID: 32897753 Originally publishedSeptember 8, 2020 KeywordsLoeys-Dietz syndromecoronary artery diseasefibromuscular dysplasiageneticsPDF download Advertisement SubjectsAcute Coronary SyndromesAneurysmGeneticsPathophysiologyVascular Disease
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