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

CAUSES Study

doi:10.1038/s41431-020-0571-6

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

CAUSES Study

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Pages (from-to)	770-782
Number of pages	13
Journal	European Journal of Human Genetics
Volume	28
Issue number	6
DOIs	https://doi.org/10.1038/s41431-020-0571-6
State	Published - 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.

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

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@article{f2378af393f449af915cdd2fdfb1ad6c,

title = "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.",

author = "{CAUSES Study} and Sophie Nambot and Laurence Faivre and Ghayda Mirzaa and Julien Thevenon and Bruel, {Ange Line} and Mosca-Boidron, {Anne Laure} and Alice Masurel-Paulet and Alice Goldenberg and {Le Meur}, Nathalie and Aude Charollais and Cyril Mignot and Florence Petit and Massimiliano Rossi and Julia Metreau and Val{\'e}rie Layet and Daniel Amram and Odile Boute-B{\'e}n{\'e}jean and Elizabeth Bhoj and Cousin, {Margot A.} and Kruisselbrink, {Teresa M.} and Lanpher, {Brendan C.} and Klee, {Eric W.} and Elise Fiala and Grange, {Dorothy K.} and Meschino, {Wendy S.} and Hiatt, {Susan M.} and Cooper, {Gregory M.} and Hilde Olivi{\'e} and Smith, {Wendy E.} and Meghan Dumas and Anna Lehman and Shelin Adam and {du Souich}, Christ{\`e}le and Elliott, {Alison M.} and Jill Mwenifumbo and Nelson, {Tanya N.} and {van Karnebeek}, Clara and Friedman, {Jan M.} and Cara Inglese and Mathilde Nizon and Renzo Guerrini and Annalisa Vetro and Kaplan, {Eitan S.} and Dolores Miramar and {Van Gils}, Julien and Patricia Fergelot and Olaf Bodamer and Herkert, {Johanna C.} and Sander Pajusalu and Dobyns, {William B.}",

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{\textquoteright}Actions R{\'e}gionales pour l{\textquoteright}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{\textquoteright}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{\textquoteright}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: {\textcopyright} 2020, The Author(s), under exclusive licence to European Society of Human Genetics.",

year = "2020",

month = jun,

day = "1",

doi = "10.1038/s41431-020-0571-6",

language = "English (US)",

volume = "28",

pages = "770--782",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Springer Nature",

number = "6",

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TY - JOUR

T1 - De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits

T2 - report of 25 new individuals and review of the literature

AU - CAUSES Study

AU - Nambot, Sophie

AU - Faivre, Laurence

AU - Mirzaa, Ghayda

AU - Thevenon, Julien

AU - Bruel, Ange Line

AU - Mosca-Boidron, Anne Laure

AU - Masurel-Paulet, Alice

AU - Goldenberg, Alice

AU - Le Meur, Nathalie

AU - Charollais, Aude

AU - Mignot, Cyril

AU - Petit, Florence

AU - Rossi, Massimiliano

AU - Metreau, Julia

AU - Layet, Valérie

AU - Amram, Daniel

AU - Boute-Bénéjean, Odile

AU - Bhoj, Elizabeth

AU - Cousin, Margot A.

AU - Kruisselbrink, Teresa M.

AU - Lanpher, Brendan C.

AU - Klee, Eric W.

AU - Fiala, Elise

AU - Grange, Dorothy K.

AU - Meschino, Wendy S.

AU - Hiatt, Susan M.

AU - Cooper, Gregory M.

AU - Olivié, Hilde

AU - Smith, Wendy E.

AU - Dumas, Meghan

AU - Lehman, Anna

AU - Adam, Shelin

AU - du Souich, Christèle

AU - Elliott, Alison M.

AU - Mwenifumbo, Jill

AU - Nelson, Tanya N.

AU - van Karnebeek, Clara

AU - Friedman, Jan M.

AU - Inglese, Cara

AU - Nizon, Mathilde

AU - Guerrini, Renzo

AU - Vetro, Annalisa

AU - Kaplan, Eitan S.

AU - Miramar, Dolores

AU - Van Gils, Julien

AU - Fergelot, Patricia

AU - Bodamer, Olaf

AU - Herkert, Johanna C.

AU - Pajusalu, Sander

AU - Dobyns, William B.

N1 - 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.

PY - 2020/6/1

Y1 - 2020/6/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41431-020-0571-6

DO - 10.1038/s41431-020-0571-6

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SN - 1018-4813

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JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 6

ER -

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

Abstract

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