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Am J Hum Genet2021;108(6):1126-1137.June 3, 2021Case Reports

Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.

Alban Ziegler1, Rémi Duclaux-Loras2, Céline Revenu3, Fabienne Charbit-Henrion4, Bernadette Begue2, Karine Duroure3, Linda Grimaud5, Anne Laure Guihot5, Valérie Desquiret-Dumas1, Mohammed Zarhrate6, Nicolas Cagnard7, Emmanuel Mas8, Anne Breton8, Thomas Edouard9, Clarisse Billon10, Michael Frank10, Estelle Colin11, Guy Lenaers5, Daniel Henrion5, Stanislas Lyonnet12, Laurence Faivre13, Yves Alembik14, Anaïs Philippe14, Bruno Moulin15, Eyal Reinstein16, Shay Tzur17, Ruben Attali17, George McGillivray18, Susan M White18, Lyndon Gallacher19, Kerstin Kutsche20, Pauline Schneeberger20, Katta M Girisha21, Shalini S Nayak21, Lynn Pais22, Reza Maroofian23, Aboulfazl Rad24, Barbara Vona25, Ehsan Ghayoor Karimiani26, Caroline Lekszas27, Thomas Haaf27, Ludovic Martin28, Frank Ruemmele29, Dominique Bonneau1, Nadine Cerf-Bensussan2, Filippo Del Bene30, Marianna Parlato31
1Department of Biochemistry and Molecular Biology, CHU d'Angers, 49000 Angers, France; University of Angers, MitoVasc, UMR CNRS 6015, INSERM 1083, 49933 Angers, France.
2Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, 75015 Paris, France.
3Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, 75012 Paris, France; Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, 75005 Paris, France.
4Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, 75015 Paris, France; Department of Pediatric Gastroenterology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, 75015 Paris, France; Department of Molecular Genetics, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, 75015 Paris, France.
5University of Angers, MitoVasc, UMR CNRS 6015, INSERM 1083, 49933 Angers, France.
6Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cité University, 75015 Paris, France.
7Bioinformatics Core Facility, INSERM-UMR 1163, Imagine Institute, 75015 Paris, France.
8IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse 31300, France; Centre de Référence des Maladies Rares Digestives, and Pediatric Clinical Research Unit, Toulouse Clinical Investigation Center INSERM U1436, Hôpital des Enfants, CHU de Toulouse, Toulouse 31300, France.
9Reference Centre for Marfan Syndrome and Reference Centre on Rare Bone Diseases, Pediatric Clinical Research Unit, Children's Hospital, Toulouse University Hospital, RESTORE, INSERM UMR1301, 31300 Toulouse, France.
10Centre de Génétique, Centre de Référence des Maladies Vasculaires Rares, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 75015 Paris, France.
11Department of Biochemistry and Molecular Biology, CHU d'Angers, 49000 Angers, France.
12Université de Paris, Imagine Institute, Laboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, 75015 Paris, France; Fédération de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, 75015 Paris, France.
13Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, 21000 Dijon, France.
14Département de Génétique Médicale, CHU de Hautepierre, 67200 Strasbourg, France.
15Nephrology and Transplantation Department, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, 67200 Strasbourg, France.
16Medical Genetics Institute, Meir Medical Center, Kfar-Saba 4428164, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
17Genomic Research Department, Emedgene Technologies, 67443 Tel Aviv, Israel.
18Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville 3052, Melbourne, VIC, Australia.
19Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville 3052, Melbourne, VIC, Australia; Department of Paediatrics, The University of Melbourne, 3010 Parkville, Melbourne, VIC, Australia.
20Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
21Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, India.
22Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
23Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, WC1N 3BG London, UK.
24Department of Otolaryngology-Head & Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany.
25Department of Otolaryngology-Head & Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany; Institute of Human Genetics, Julius Maximilians University Würzburg, 97074 Würzburg, Germany.
26Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace London, SW17 ORE London, UK; Innovative Medical Research Center, Mashhad Branch, Islamic Azdad University, Mashhad 9133736351, Iran.
27Institute of Human Genetics, Julius Maximilians University Würzburg, 97074 Würzburg, Germany.
28University of Angers, MitoVasc, UMR CNRS 6015, INSERM 1083, 49933 Angers, France; Department of Dermatology, CHU d'Angers, 49000 Angers, France.
29Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, 75015 Paris, France; Department of Pediatric Gastroenterology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, 75015 Paris, France.
30Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, 75012 Paris, France; Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, 75005 Paris, France. Electronic address: filippo.del-bene@inserm.fr.
31Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, 75015 Paris, France. Electronic address: marianna.parlato@inserm.fr.
PubMed PMC DOI PDF

Abstract

Dysregulated transforming growth factor TGF-β signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and d…

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