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

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De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature.
European Journal of Human Genetics ( IF 5.2 ) Pub Date : 2020-01-31 , DOI: 10.1038/s41431-020-0571-6
Sophie Nambot _{1,

2,

3} , Laurence Faivre _{1,

2,

3} , Ghayda Mirzaa _{4,

5} , Julien Thevenon _{1,

2,

3,

6} , Ange-Line Bruel _{1,

2,

6} , Anne-Laure Mosca-Boidron _{1,

2,

6} , Alice Masurel-Paulet _{1,

3} , Alice Goldenberg ₇ , Nathalie Le Meur ₇ , Aude Charollais ₈ , Cyril Mignot ₉ , Florence Petit ₁₀ , Massimiliano Rossi ₁₁ , Julia Metreau ₁₂ , Valérie Layet ₁₃ , Daniel Amram ₁₄ , Odile Boute-Bénéjean ₁₀ , Elizabeth Bhoj _{15,

16} , Margot A Cousin _{17,

18} , Teresa M Kruisselbrink _{17,

19} , Brendan C Lanpher _{17,

19} , Eric W Klee _{17,

18,

19} , Elise Fiala ₂₀ , Dorothy K Grange ₂₁ , Wendy S Meschino ₂₂ , Susan M Hiatt ₂₃ , Gregory M Cooper ₂₃ , Hilde Olivié ₂₄ , Wendy E Smith ₂₅ , Meghan Dumas ₂₅ , Anna Lehman ₂₆ , , Cara Inglese ₂₆ , Mathilde Nizon ₂₇ , Renzo Guerrini ₂₈ , Annalisa Vetro ₂₈ , Eitan S Kaplan ₅ , Dolores Miramar ₂₉ , Julien Van Gils ₃₀ , Patricia Fergelot ₃₁ , Olaf Bodamer ₃₂ , Johanna C Herkert ₃₃ , Sander Pajusalu ₃₄ , Katrin Õunap ₃₄ , James J Filiano ₃₅ , Thomas Smol ₃₆ , Amélie Piton ₃₇ , Bénédicte Gérard ₃₇ , Sandra Chantot-Bastaraud _{9,

38} , Thierry Bienvenu ₃₉ , Dong Li ₁₇ , Jane Juusola ₄₀ , Koen Devriendt ₄₁ , Frederic Bilan ₄₂ , Charlotte Poé ₂ , Martin Chevarin ₂ , Thibaud Jouan ₂ , Emilie Tisserant ₂ , Jean-Baptiste Rivière _{2,

3,

6} , Frédéric Tran Mau-Them _{2,

6} , Christophe Philippe _{2,

6} , Yannis Duffourd _{2,

6} , William B Dobyns ₄ , Robert Hevner ₄ , Christel Thauvin-Robinet _{1,

2,

3,

6}

Affiliation

Centre de Génétique et Centre de Référence Maladies Rares (Anomalies du Développement de l'Interrégion Est), Hôpital d'Enfants, CHU Dijon Bourgogne, Dijon, France.
Inserm UMR 1231 GAD (Génétique des Anomalies du Développement), Université de Bourgogne, Dijon, France.
Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD), CHU Dijon Bourgogne et Université de Bourgogne-Franche Comté, Dijon, France.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
Department of Pediatrics, University of Washington, Seattle, WA, USA.
UF Innovation en diagnostic génomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.
Service de génétique, CHU de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée, Rouen, France.
Service de Pédiatrie, CHU Rouen Normandie, Rouen, France.
Service de Génétique et d'Embryologie Médicales, Hôpital Trousseau, Paris, France.
Clinique de Génétique Guy Fontaine, Pôle de Biologie Pathologie Génétique, Hôpital Jeanne de Flandre, CHU de Lille, F-59000, Lille, France.
Service de Génétique, Hospices Civils de Lyon, Centre de Recherche en Neurosciences Lyon, INSERM U1028, CNRS UMR5292, GENDEVTeam, Bron, France.
Service de Neurologie Pédiatrique, Hôpital du Kremlin Bicêtre, Paris, France.
Service de Génétique, Groupe Hospitalier du Havre, Le Havre, France.
Unité de Génétique Médicale, CHIC de Créteil, Créteil, France.
Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA.
Department of Clinical Genomics, Mayo Clinic, Rochester, MN, 55905, USA.
Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA.
Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA.
Genetics Program, North York General Hospital, Toronto, ON, Canada.
601 Genome Way, HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
Centre for Developmental Disorders, University Hospitals Leuven, Leuven, Belgium.
Department of Pediatrics, The Barbara Bush Children's Hospital, Maine Medical Center, Portland, OR, USA.
Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6H 3N1, Canada.
Service de Génétique Médicale, CHU de Nantes, Nantes, France.
Neuroscience Department, Children's Hospital Meyer-University of Florence, Florence, Italy.
Genetics Unit, Biochemistry Service, Hospital Miguel Servet, Zaragoza, Spain.
Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France.
Laboratoire de génétique moléculaire, CHU de Bordeaux, Bordeaux, France.
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
Department of Clinical Genetics, Tartu University Hospital and Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
Departments of Pediatrics and Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
Institut de Génétique Médicale, CHRU de Lille, Lille, France.
Laboratoire de diagnostic génétique, Hôpital Civil, CHRU Strasbourg, Strasbourg, France.
Service de Génétique et d'Embryologie Médicales, INSERM U933, Paris, France.
Service de génétique et biologie moléculaire, Hôpital Cochin, CHU Paris Centre, Paris, France.
GeneDx, Gaithersburg, MD, USA.
Center for Human Genetics, University of Leuven, Leuven, Belgium.
Laboratoire de Génétique, Service de Génétique, CHU Poitiers, Poitiers, France.

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.

中文翻译：

从头开始的TBR1变异会导致具有ID和自闭症特征的神经认知表型：25个新个体的报告和文献综述。

TBR1是一种在大脑皮层中表达的T-box转录因子，它调节自闭症谱系障碍（ASD）的几种候选基因的表达。尽管自2011年以来在功能和临床报告中已将TBR1报告为ASD和智力障碍（ID）的高置信度风险基因，但直到最近，TBR1才在OMIM数据库中被记录为人类疾病基因。目前，与TBR1变异相关的神经发育障碍和大脑结构异常尚未得到很好的表征。通过国际数据共享，我们收集了来自25个未报告人员的数据，并将其与文献数据进行了比较。我们通过分析MRI图像评估了7个人的结构性脑部异常，并将其与TBR1突变小鼠中观察到的异常进行了比较。该表型包括所有个人的ID，其中有76％与自闭症特征相关。无法识别可识别的面部表型。MRI分析显示前连合减少，并提出了新的特征，包括海马发育异常和新皮层发育不全。该报告支持TBR1在与自闭症特征相关的ID中的作用，并建议人类中新的结构性脑畸形。我们希望这项工作将有助于遗传学家解释TBR1变异并诊断ASD先证者。该报告支持TBR1在与自闭症特征相关的ID中的作用，并建议人类中新的结构性脑畸形。我们希望这项工作将有助于遗传学家解释TBR1变异并诊断ASD先证者。该报告支持TBR1在与自闭症特征相关的ID中的作用，并建议人类中新的结构性脑畸形。我们希望这项工作将有助于遗传学家解释TBR1变异并诊断ASD先证者。

更新日期：2020-01-31

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