De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature

Sophie Nambot, Centre de Génétique et Centre de Référence Maladies Rares (Anomalies du Développement de l'Interrégion Est), Hôpital d'Enfants, CHU Dijon Bourgogne, Dijon, France.
Laurence Faivre, Centre de Génétique et Centre de Référence Maladies Rares (Anomalies du Développement de l'Interrégion Est), Hôpital d'Enfants, CHU Dijon Bourgogne, Dijon, France.
Ghayda Mirzaa, Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
Julien Thevenon, Centre de Génétique et Centre de Référence Maladies Rares (Anomalies du Développement de l'Interrégion Est), Hôpital d'Enfants, CHU Dijon Bourgogne, Dijon, France.
Ange-Line Bruel, Centre de Génétique et Centre de Référence Maladies Rares (Anomalies du Développement de l'Interrégion Est), Hôpital d'Enfants, CHU Dijon Bourgogne, Dijon, France.
Anne-Laure Mosca-Boidron, Centre de Génétique et Centre de Référence Maladies Rares (Anomalies du Développement de l'Interrégion Est), Hôpital d'Enfants, CHU Dijon Bourgogne, Dijon, France.
Alice Masurel-Paulet, Centre de Génétique et Centre de Référence Maladies Rares (Anomalies du Développement de l'Interrégion Est), Hôpital d'Enfants, CHU Dijon Bourgogne, Dijon, France.
Alice Goldenberg, Service de génétique, CHU de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée, Rouen, France.
Nathalie Le Meur, Service de génétique, CHU de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée, Rouen, France.
Aude Charollais, Service de Pédiatrie, CHU Rouen Normandie, Rouen, France.
Cyril Mignot, Service de Génétique et d'Embryologie Médicales, Hôpital Trousseau, Paris, France.
Florence Petit, Clinique de Génétique Guy Fontaine, Pôle de Biologie Pathologie Génétique, Hôpital Jeanne de Flandre, CHU de Lille, F-59000, Lille, France.
Massimiliano Rossi, Service de Génétique, Hospices Civils de Lyon, Centre de Recherche en Neurosciences Lyon, INSERM U1028, CNRS UMR5292, GENDEVTeam, Bron, France.
Julia Metreau, Service de Neurologie Pédiatrique, Hôpital du Kremlin Bicêtre, Paris, France.
Valérie Layet, Service de Génétique, Groupe Hospitalier du Havre, Le Havre, France.
Daniel Amram, Unité de Génétique Médicale, CHIC de Créteil, Créteil, France.
Odile Boute-Bénéjean, Clinique de Génétique Guy Fontaine, Pôle de Biologie Pathologie Génétique, Hôpital Jeanne de Flandre, CHU de Lille, F-59000, Lille, France.
Elizabeth Bhoj, Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Margot A. Cousin, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
Teresa M. Kruisselbrink, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
Brendan C. Lanpher, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
Eric W. Klee, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
Elise Fiala, Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA.
Dorothy K. Grange, Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA.
Wendy S. Meschino, Genetics Program, North York General Hospital, Toronto, ON, Canada.
Susan M. Hiatt, 601 Genome Way, HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
Gregory M. Cooper, 601 Genome Way, HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
Hilde Olivié, Centre for Developmental Disorders, University Hospitals Leuven, Leuven, Belgium.
Wendy E. Smith, Department of Pediatrics, The Barbara Bush Children's Hospital, Maine Medical Center, Portland, OR, USA.
Meghan Dumas, Department of Pediatrics, The Barbara Bush Children's Hospital, Maine Medical Center, Portland, OR, USA.
Anna Lehman, Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6H 3N1, Canada.

Abstract

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands.