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

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.

• Authors: Sophie Nambot, Laurence Faivre, Ghayda Mirzaa, Julien Thevenon, Ange-Line Bruel, Anne-Laure Mosca-Boidron, Alice Masurel-Paulet, Alice Goldenberg, Nathalie Le Meur, Aude Charollais, Cyril Mignot, Florence Petit, Massimiliano Rossi, Julia Metreau, Valérie Layet, Daniel Amram, Odile Boute-Bénéjean, Elizabeth Bhoj, Margot A Cousin, Teresa M Kruisselbrink, Brendan C Lanpher, Eric W Klee, Elise Fiala, Dorothy K Grange, Wendy S Meschino, Susan M Hiatt, Gregory M Cooper, Hilde Olivié, Wendy E Smith, Meghan Dumas, Anna Lehman, CAUSES Study, Cara Inglese, Mathilde Nizon, Renzo Guerrini, Annalisa Vetro, Eitan S Kaplan, Dolores Miramar, Julien Van Gils, Patricia Fergelot, Olaf Bodamer, Johanna C Herkert, Sander Pajusalu, Katrin Õunap, James J Filiano, Thomas Smol, Amélie Piton, Bénédicte Gérard, Sandra Chantot-Bastaraud, Thierry Bienvenu, Dong Li, Jane Juusola, Koen Devriendt, Frederic Bilan, Charlotte Poé, Martin Chevarin, Thibaud Jouan, Emilie Tisserant, Jean-Baptiste Rivière, Frédéric Tran Mau-Them, Christophe Philippe, Yannis Duffourd, William B Dobyns, Robert Hevner, Christel Thauvin-Robinet
• Journal: European journal of human genetics : EJHG (Eur J Hum Genet) Vol. 28 Issue 6 Pg. 770-782 (06 2020) ISSN: 1476-5438 [Electronic] England
• PMID: 32005960 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)

Chemical References

• T-Box Domain Proteins
• TBR1 protein, human

Topics

• Adolescent
• Adult
• Animals
• Autistic Disorder (genetics, pathology)
• Child
• Child, Preschool
• Cognition
• Craniofacial Abnormalities (genetics, pathology)
• Female
• Hippocampus (diagnostic imaging, pathology)
• Humans
• Intellectual Disability (genetics, pathology)
• Male
• Mice
• Mutation
• Neocortex (diagnostic imaging, pathology)
• Phenotype
• Syndrome
• T-Box Domain Proteins (genetics, metabolism)