Authors
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YBA Wan
Genetics Research Centre, Molecular and Clinical Sciences Research Institute, St. George’s University of London, United Kingdom
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M Simpson
Division of Genetics and Molecular Medicine, Kings College London, United Kingdom
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E Dulfer
Department of Genetics, University Medical Center Groningen, The Netherlands
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DPS Osborn
Genetics Research Centre, Molecular and Clinical Sciences Research Institute, St. George’s University of London, United Kingdom
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WS Kerstjens-Frederikse
Department of Genetics, University Medical Center Groningen, The Netherlands
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YJ Vos
Department of Genetics, University Medical Center Groningen, The Netherlands
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A Pinard
Department of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston McGovern Medical School, Texas, USA
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E Regalado
Department of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston McGovern Medical School, Texas, USA
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DC Guo
Department of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston McGovern Medical School, Texas, USA
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C Boileau
Laboratory of Vascular Translational Science, INSERM U1368, Paris, France & Centre de référence pour le syndrome de Marfan et apparentés, APHP hospital Bichat, Paris, France & Université Paris Diderot, Paris France & Department de Genetique, APHP, Hopital Bichat Paris, France
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G Jondeau
Laboratory of Vascular Translational Science, INSERM U1368, Paris, France & Centre de référence pour le syndrome de Marfan et apparentés, APHP hospital Bichat, Paris, France & Université Paris Diderot, Paris France & Service de Cardiologie, APHP, Hopital Bichat, Paris, France
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L Benarroch
Laboratory of Vascular Translational Science, INSERM U1368, Paris, France
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B Loeys
Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp, Belgium
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I Luyckx
Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp, Belgium
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L Van Laer
Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp, Belgium
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A Verstraeten
Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp, Belgium
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J DeBacker
Adult Congenital Heart Disease and Cardiogenetics, Ghent University Hospital, Ghent, Belgium
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V Ramachandran
Genetics Research Centre, Molecular and Clinical Sciences Research Institute, St. George’s University of London, United Kingdom
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QM Ashraf
NHLI, Imperial College, London, United Kingdom
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L Lau
NHLI, Imperial College, London, United Kingdom
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M Garcia
Genetics Research Centre, Molecular and Clinical Sciences Research Institute, St. George’s University of London, United Kingdom
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J Gaer
Royal Brompton & Harefield Hospitals NHS Foundation Trust, London, United Kingdom
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J Bharj
Genetics Research Centre, Molecular and Clinical Sciences Research Institute, St. George’s University of London, United Kingdom
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J Sneddon
East Surrey Hospital, Redhill, Surrey, United Kingdom
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E Fisher
The Park Surgery, Albion Way, Horsham, Surrey, United Kingdom
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J Dean
Clinical Genetics, NHS Grampian, Foresterhill, Aberdeen, United Kingdom
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Y Isekame
Genetics Research Centre, Molecular and Clinical Sciences Research Institute, St. George’s University of London, United Kingdom
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A Saggar
Clinical Genetics Unit, St. George’s University Hospitals NHS Foundation Trust, United Kingdom
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D Milewicz
Department of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston McGovern Medical School, Texas, USA
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M Jahangiri
Department of Cardiothoracic Surgery, St. George’s University Hospitals NHS Foundation Trust, United Kingdom & Cardiology Academic Group, Cardiology Department, St. George’s, University Hospitals, NHS Foundation Trust, United Kingdom
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ER Behr
Cardiology Academic Group, Cardiology Department, St. George’s, University Hospitals, NHS Foundation Trust, United Kingdom
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A Child
Genetics Research Centre, Molecular and Clinical Sciences Research Institute, St. George’s University of London, United Kingdom, & Marfan Trust, Guy Scadding Building, London, United Kingdom
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A Smith
Academic Department of Vascular Surgery, Cardiovascular Division, BHF Centre of Research Excellence, Kings College London, United Kingdom
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JA Aragon-Martin
Genetics Research Centre, Molecular and Clinical Sciences Research Institute, St. George’s University of London, United Kingdom & NHLI, Imperial College, London, United Kingdom
Keywords:
FTAAD, LMOD1, smooth muscle contraction, WES, variants, Familial Thoracic Aortic Aneurysm and Dissection, diagnosis
Abstract
Objective
Thoracic Aortic Aneurysm & Dissection (TAAD) can arise at any time without previous warnings and with fatal consequences. We seek to determine the genetic cause of TAAD in a UK multi-generational Caucasian family.
Approach
Whole exome sequencing was performed and analysed on three affected individuals. Both in vitro and in vivo studies evaluated functionally the role of the candidate gene.
Results
Twenty-five variants in LMOD1 were identified from 1751 probands from UK and international cohorts, of which six were identified to be most deleterious by in silico validation. N-terminus variants in the TMBS domain & C-terminus variants in the WH2 domain were enriched in their respective domains in the complete TAAD patient cohort versus the gnomAD genetic database. Myofibroblasts from the proband with variant Val595Ala demonstrated reduced nucleation of actin filaments, mislocalization of LMOD1 protein, and impaired contractility. Knockdown of paralogs lmod1a/lmod1b in zebrafish demonstrated delayed development of the aortic precursors (pharyngeal arches), rescued by co-injections with wild-type LMOD1 mRNA. Conversely, this zebrafish knockdown could not be fully rescued by the mutant c.1784T>C [p.(Val595Ala)] containing LMOD1 mRNA, strongly suggesting this variant is pathogenic for TAAD.
Conclusions
This study suggests that variant Val595Ala predisposes to TAAD due to abnormal LMOD1 functionality. Future variants identified in the WH2 domain may also delay actin polymerization, compromising actin length, dynamics and interaction with myosin in the vascular smooth muscle contraction pathway. This study strongly supports a role for LMOD1 in development and maintenance of smooth muscle through its control of the cells’ actin cytoskeleton.
