Mutations in TBR1 gene leads to cortical malformations and intellectual disability

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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.

Introduction

Huge developments in next generation sequencing have significantly increased the number of genes identified in neurodevelopmental disorders. Neurological diseases are mostly Mendelian disorders and regroup a wide range of phenotypes, from early cortical impairments leading to cortical malformations, to later deregulation of neurodevelopmental processes, linked mostly to intellectual disability, autism spectrum disorder and epilepsy. A growing knowledge of the genetic basis of these diseases has expanded the array of genes implicated in neurodevelopmental conditions and also helped to optimize the genotype-phenotype correlation and the delineation of new phenotypes. De novo mutations have been shown to be a major cause of severe early-onset genetic disorders, such as intellectual disability, autism spectrum disorder, and other developmental diseases (Acuna-Hidalgo et al., 2016).

The development of next generation sequencing has also highlighted the large heterogeneity in the clinical presentations for a single disease gene, with consequently, a limitation of molecular classification of neurological diseases. Genes identified in intellectual disability or epilepsy have also been implicated in cortical malformation disorders.

Malformations of cortical development (MCD) are rare diseases of unknown prevalence and thought to be largely genetic in origin. The diagnosis of MCD relies on magnetic resonance imaging (MRI) performed on individuals with intellectual disability combined, or not, with autism spectrum disorder and/or epilepsy. MCD are mostly reported in sporadic cases due to de novo mutations, although numerous genes are known with an autosomal recessive inheritance pattern. Recently, a large number of new MCD genes have been described in patients with intellectual disability. Of these, KIF5C mutations identified in frontal pachygyria or polymicrogyria (Cavallin et al., 2016; Willemsen et al., 2014) or NEDD4L mutations, found in periventricular nodular heterotopia (Kato et al., 2017; Broix et al., 2016; Dibbens et al., 2007; Epi4K Consortium et al., 2013; Vanli-Yavuz et al., 2015; Wu et al., 2015).

Variations in the clinical phenotypes for a given candidate gene and the large number of genes implicated in each neurological disorder, as discovered through next generation sequencing, has resulted in challenges in diagnosis, prenatal testing and genetic counseling.

Here, we describe two unrelated patients with a simplification of frontal pachygyria, sharing the same de novo frameshift mutation in the TBR1 gene. The first individual has been investigated in our laboratory, whereas the second was previously published for intellectual disability (Gilissen et al., 2014a) and subsequently characterized by a cortical malformation. TBR1 has been previously described in developmental delay, autism spectrum disorder and intellectual disability without brain malformations (Deriziotis et al., 2014a; Gilissen et al., 2014a; Neale et al., 2012a; O'Roak et al., 2012a; Belengeanu et al., 2014). These two patients enlarge the spectrum of TBR1 mutations to include cortical malformations.

Section snippets

Patients and methods

Patient 1 was enrolled in the Developmental Brain Cortical Malformation Research Program in Necker Enfants Malades – Imagine Institute with IRB approval. The second patient, previously published in a large paper on genomic sequencing in ID/ASD, was reanalyzed by the investigators and one of the authors of this paper. The investigators reviewed all clinical, neuroimaging and molecular data.

Molecular analysis for patient 1 was performed using trio-based exome sequencing on peripheral blood DNA

Patient 1

The patient is the first boy of a non-consanguineous Bulgarian couple. There was no family history of intellectual disability, congenital anomalies or neurological disorders. Pregnancy was normal. He was born at full term, via vaginal delivery with normal neonatal parameters, i.e birth weight 4050 g. (+2 SD), birth length 52.5 cm (+1 SD), and birth OFC 34 cm (−1 SD). Neonatal period was normal except for gastroesophageal reflux complicated with esophagitis.

The proband initially presented at 9

Discussion

T-brain-1 (TBR1), a neuron-specific transcription factor critical for forebrain development, has been identified as a rare cause of sporadic autism (ASD) and intellectual disability (ID). To date, only 6 de novo TBR1 mutations have been reported in sporadic cases of ASD (Deriziotis et al., 2014b; Neale et al., 2012b; O'Roak et al., 2012b) (De Rubeis et al., 2014; Iossifov et al., 2014). On the other hand, rare inherited TBR1 mutations were identified in probands with sporadic ASD, although

Funding sources

Research reported in this publication was supported by the Agence Nationale de la Recherche (MC, AB and NBB was supported by ANR-16-CE16-011), the Fondation Maladies Rares, and DESIRE (grant agreement 602531), and COST Action Proposal OC-2016-1-20862 " European Network on Brain Malformations ".

Acknowledgements

We would like to thank the patients and their families for their contribution to our research and the Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience for their collaboration. This study was performed by INSERM UMR-1163, Embryology and genetics of congenital malformations.

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