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


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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.

Original languageEnglish (US)
Pages (from-to)770-782
Number of pages13
JournalEuropean Journal of Human Genetics
Issue number6
StatePublished - Jun 1 2020

Bibliographical note

Funding Information:
Acknowledgements This study makes use of data shared through the PhenomeCentral repository. Funding for PhenomeCentral was provided by Genome Canada and Canadian Institute of Health Research (CIHR). Research reported in this publication was supported by the French Ministry of Health (PHRC national 2008/2008-A00515-50), the Regional Council of Burgundy/Dijon University hospital (Plan d’Actions Régionales pour l’Innovation PARI 2012, AOI 2013), the European Union through the PO FEDER-FSE Bourgogne 2014/2020 programs (FEDER 2015), the National Institute of Neurological Disorders and Stroke (NINDS) under award number K08NS092898 and Jordan’s Guardian Angels (to GM), by NIH Grants R01 NS092339 and R01 NS085081 (to RFH), and by NHGRI grant UM1HG007301 to GMC. The CAUSES Study is funded by Mining for Miracles, British Columbia Children’s Hospital Foundation and Genome British Columbia. Several authors of this publication are members of the European Reference Network for Developmental Anomalies and Intellectual Disability (ERN-ITHACA). Proofreading of the manuscript was provided by Suzanne Rankin from the Dijon University Hospital.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to European Society of Human Genetics.


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