[en] Haploinsufficiency of TRIP12 causes a neurodevelopmental disorder characterized by intellectual disability associated with epilepsy, autism spectrum disorder and dysmorphic features, also named Clark-Baraitser syndrome. Only a limited number of cases have been reported to date. We aimed to further delineate the TRIP12-associated phenotype and objectify characteristic facial traits through GestaltMatcher image analysis based on deep-learning algorithms in order to establish a TRIP12 gestalt. 38 individuals between 3 and 66 years (F = 20, M = 18) - 1 previously published and 37 novel individuals - were recruited through an ERN ITHACA call for collaboration. 35 TRIP12 variants were identified, including frameshift (n = 15) and nonsense (n = 6) variants, as well as missense (n = 5) and splice (n = 3) variants, intragenic deletions (n = 4) and two multigene deletions disrupting TRIP12. Though variable in severity, global developmental delay was noted in all individuals, with language deficit most pronounced. About half showed autistic features and susceptibility to obesity seemed inherent to this disorder. A more severe expression was noted in individuals with a missense variant. Facial analysis showed a clear gestalt including deep-set eyes with narrow palpebral fissures and fullness of the upper eyelids, downturned corners of the mouth and large, often low-set ears with prominent earlobes. We report the largest cohort to date of individuals with TRIP12 variants, further delineating the associated phenotype and introducing a facial gestalt. These findings will improve future counseling and patient guidance.
Disciplines :
Human health sciences: Multidisciplinary, general & others
Author, co-author :
Aerden, Mio ; Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium. mio.aerden@uzleuven.be
Denommé-Pichon, Anne-Sophie ; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France ; UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France
Bonneau, Dominique; Department of Biochemistry and Genetics, Angers University Hospital and UMR CNRS 6015-INSERM 1083, Angers, France
Bruel, Ange-Line ; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France ; UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France
Delanne, Julian; UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France ; Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France
Gérard, Bénédicte; Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Mazel, Benoît ; UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France ; Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France
Philippe, Christophe ; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France ; UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France
Pinson, Lucile; Service de génétique - Centre de Référence Anomalies du Développement CLAD Sud Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
Prouteau, Clément; Department of Biochemistry and Genetics, Angers University Hospital and UMR CNRS 6015-INSERM 1083, Angers, France
Putoux, Audrey; Centre de Référence Anomalies du Développement et Syndromes Malformatifs Centre Est, Hospices Civils de Lyon, Lyon, France
Tran Mau-Them, Frédéric ; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France ; UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France
Viora-Dupont, Éléonore ; UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France ; Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France
Vitobello, Antonio ; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France ; UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France
Ziegler, Alban; Department of Biochemistry and Genetics, Angers University Hospital and UMR CNRS 6015-INSERM 1083, Angers, France
Piton, Amélie ; Hôpitaux Universitaires de Strasbourg, Laboratoire de Diagnostic Génétique, Strasbourg, France
Isidor, Bertrand; Service de Genetique Medicale, CHU de Nantes & Inserm, CNRS, Universite de Nantes, l'institut du thorax, Nantes, France
Francannet, Christine; Service de Genetique Medicale, CHU de Clermont-Ferrand, Clermont-Ferrand, France
Maillard, Pierre-Yves ; Service de Genetique Medicale, IGMA, Hopitaux Universitaires de Strasbourg, Strasbourg, France
Julia, Sophie; Service de Génétique Clinique, CHU Toulouse, Toulouse, France
Philippe, Anais; Service de Genetique Medicale, IGMA, Hopitaux Universitaires de Strasbourg, Strasbourg, France
Schaefer, Elise; Service de Genetique Medicale, IGMA, Hopitaux Universitaires de Strasbourg, Strasbourg, France
Koene, Saskia; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Ruivenkamp, Claudia; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Hoffer, Mariette ; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Legius, Eric; Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
Theunis, Miel; Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
Keren, Boris; Genetic Department, Pitié-Salpêtrière Hospital, AP-HP.Sorbonne Université, Paris, France
Charles, Perrine; Genetic Department, Pitié-Salpêtrière Hospital, AP-HP.Sorbonne Université, Paris, France
Courtin, Thomas; Genetic Department, Pitié-Salpêtrière Hospital, AP-HP.Sorbonne Université, Paris, France
Misra-Isrie, Mala; Department of Human Genetics, Amsterdam University Medical Centers, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
van Haelst, Mieke ; Department of Human Genetics, Amsterdam University Medical Centers, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Waisfisz, Quinten; Department of Human Genetics, Amsterdam University Medical Centers, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Wieczorek, Dagmar; Heinrich-Heine-Universität, Institut für Humangenetik, Düsseldorf, Germany
Schmetz, Ariane; Heinrich-Heine-Universität, Institut für Humangenetik, Düsseldorf, Germany
Herget, Theresia; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Kortüm, Fanny; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Lisfeld, Jasmin; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Debray, François-Guillaume ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Maladies métaboliques d'origine génétique
Bramswig, Nuria C; Heinrich-Heine-Universität, Institut für Humangenetik, Düsseldorf, Germany
Atallah, Isis ; Lausanne University Hospital, Division of Genetic Medicine, Lausanne, Switzerland
Fodstad, Heidi; Lausanne University Hospital, Division of Genetic Medicine, Lausanne, Switzerland
Jouret, Guillaume; National Center of Genetics (NCG), Laboratoire national de santé (LNS), Dudelange, Luxembourg
Almoguera, Berta; Fundación Jiménez Díaz Hospital, Department of Genetics and Genomics, Madrid, Spain
Tahsin-Swafiri, Saoud ; Fundación Jiménez Díaz Hospital, Department of Genetics and Genomics, Madrid, Spain
Santos-Simarro, Fernando; Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain ; Molecular Diagnostics and Clinical Genetics Unit (UDMGC), Hospital Universitari Son Espses, IdISBa, Palma, Spain
Palomares-Bralo, Maria; Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain
López-González, Vanesa; Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Sección de Genética Médica, Servicio de Pediatría, Murcia, Spain
Kibaek, Maria; Pediatric Department, Odense University Hospital, Odense, Denmark
Tørring, Pernille M; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
Renieri, Alessandra; Medical Genetics, University of Siena, Siena, Italy ; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy ; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy
Bruno, Lucia Pia; Medical Genetics, University of Siena, Siena, Italy ; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy
Õunap, Katrin ; Tartu University Hospital, Genetic and Personalized Medicine Clinic, Department of Clinical Genetics, Tartu, Estonia ; University of Tartu, Institute of Clinical Medicine, Tartu, Estonia
Wojcik, Monica; Department of Pediatrics, Boston Children's Hospital, Divisions of Newborn Medicine and Genetics and Genomics, Boston, MA, USA ; The Broad Institute of MIT and Harvard, Cambridge, MA, USA
Hsieh, Tzung-Chien; Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
Krawitz, Peter; Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
Van Esch, Hilde ; Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium. hilde.vanesch@uzleuven.be
NHLBI - National Heart Lung and Blood Institute FWO - Fonds Wetenschappelijk Onderzoek Vlaanderen
Funding text :
HVE is supported by a Senior Clinical Investigator fellowship of the Fonds voor Wetenschappelijk Onderzoek (FWO) Flanders. Almost all authors are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516]. K.Õ is supported by grant from the Estonian Research Council (grant PRG471). The Broad Center for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute.
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