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Eur J Med Genet. 2018 Sep 27. pii: S1769-7212(17)30791-7. doi: 10.1016/j.ejmg.2018.09.012. [Epub ahead of print]

Mutations in TBR1 gene leads to cortical malformations and intellectual disability.

Author information

1
Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163, Imagine Institute, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Neurology, APHP- Necker Enfants Malades University Hospital, Paris, France.
2
Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
3
Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
4
Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163, Imagine Institute, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
5
Pediatric Radiology APHP- Necker Enfants Malades University Hospital, Paris, France; INSERM U1000 and UMR 1163, Institut Imagine, Paris, France.
6
Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163, Imagine Institute, Paris, France; INSERM UMR-1163, Translational Genetics, Institut Imagine, Paris, France.
7
Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163, Imagine Institute, Paris, France; INSERM UMR-1163, Translational Genetics, Institut Imagine, Paris, France; Bioinformatic Platform, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
8
Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163, Imagine Institute, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Neurology, APHP- Necker Enfants Malades University Hospital, Paris, France; Reference Center "Déficiences Intellectuelles de Causes Rares", APHP- Necker Enfantes Malades University Hospital, Paris, France. Electronic address: nadia.bahi-buisson@nck.aphp.fr.

Abstract

The advent of next generation sequencing has improved gene discovery in neurodevelopmental disorders. A greater understanding of the genetic basis of these disorders has expanded the spectrum of pathogenic genes, thus enhancing diagnosis and therapeutic management. Genetic overlap between distinct neurodevelopmental disorders has also been revealed, which can make determining a strict genotype-phenotype correlation more difficult. Intellectual disability and cortical malformations are two neurodevelopmental disorders particularly confronted by this difficulty. Indeed, for a given pathogenic gene, intellectual disability can be associated, or not, with cortical malformations. Here, we report for the first time, two individuals with the same de novo mutation in TBR1, leading to a frameshift starting at codon Thr532, and resulting in a premature stop codon 143 amino acids downstream (c.1588_1594dup, p.(Thr532Argfs*144)). These individuals presented with a developmental encephalopathy characterized by frontal pachygyria and severe intellectual disability. Remarkably, 11 TBR1 gene mutations were previously reported in intellectual disability and autism spectrum disorders. Our study supports the observation that TBR1-related disorders range from intellectual disability to frontal pachygyria. We also highlight the need for first-line, good quality neuroimaging for patients with intellectual disability.

KEYWORDS:

Autistic spectrum disorder; Cortical malformation; Developmental delay; Intellectual disability; Neurodevelopmental disorder; TBR1

PMID:
30268909
DOI:
10.1016/j.ejmg.2018.09.012

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